A reciprocal translocation of the ABL1 gene to the BCR gene results in the expression of the oncogenic BCR-ABL1 fusion protein, which characterizes human chronic myeloid leukemia (CML), a myeloproliferative disorder considered invariably fatal until the introduction of the imatinib family of tyrosine kinase inhibitors (TKI). Nonetheless, insensitivity of CML stem cells to TKI treatment and intrinsic or acquired resistance are still frequent causes for disease persistence and blastic phase progression experienced in patients after initial successful therapies. Here, we investigated a possible role for the MAPK15/ERK8 kinase in BCR-ABL1-dependent autophagy, a key process for oncogene-induced leukemogenesis. In this context, we showed the ability of MAPK15 to physically recruit the oncogene to autophagic vesicles, confirming our hypothesis of a biologically relevant role for this MAP kinase in signal transduction by this oncogene. Indeed, by modeling BCR-ABL1 signaling in HeLa cells and taking advantage of a physiologically relevant model for human CML, i.e. K562 cells, we demonstrated that BCR-ABL1-induced autophagy is mediated by MAPK15 through its ability to interact with LC3-family proteins, in a LIR-dependent manner. Interestingly, we were also able to interfere with BCR-ABL1-induced autophagy by a pharmacological approach aimed at inhibiting MAPK15, opening the possibility of acting on this kinase to affect autophagy and diseases depending on this cellular function. Indeed, to support the feasibility of this approach, we demonstrated that depletion of endogenous MAPK15 expression inhibited BCR-ABL1-dependent cell proliferation, in vitro, and tumor formation, in vivo, therefore providing a novel "druggable" link between BCR-ABL1 and human CML.
A reciprocal translocation of the ABL1 gene to the BCR gene results in the expression of the oncogenic BCR-ABL1 fusion protein, which characterizes humanchronic myeloid leukemia (CML), a myeloproliferative disorder considered invariably fatal until the introduction of the imatinib family of tyrosine kinase inhibitors (TKI). Nonetheless, insensitivity of CML stem cells to TKI treatment and intrinsic or acquired resistance are still frequent causes for disease persistence and blastic phase progression experienced in patients after initial successful therapies. Here, we investigated a possible role for the MAPK15/ERK8 kinase in BCR-ABL1-dependent autophagy, a key process for oncogene-induced leukemogenesis. In this context, we showed the ability of MAPK15 to physically recruit the oncogene to autophagic vesicles, confirming our hypothesis of a biologically relevant role for this MAP kinase in signal transduction by this oncogene. Indeed, by modeling BCR-ABL1 signaling in HeLa cells and taking advantage of a physiologically relevant model for humanCML, i.e. K562 cells, we demonstrated that BCR-ABL1-induced autophagy is mediated by MAPK15 through its ability to interact with LC3-family proteins, in a LIR-dependent manner. Interestingly, we were also able to interfere with BCR-ABL1-induced autophagy by a pharmacological approach aimed at inhibiting MAPK15, opening the possibility of acting on this kinase to affect autophagy and diseases depending on this cellular function. Indeed, to support the feasibility of this approach, we demonstrated that depletion of endogenous MAPK15expression inhibited BCR-ABL1-dependent cell proliferation, in vitro, and tumor formation, in vivo, therefore providing a novel "druggable" link between BCR-ABL1 and humanCML.
Entities:
Keywords:
BCR-ABL1; LC3B; MAP kinases; autophagy; signal transduction
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by excessive accumulation of apparently normal myeloid cells, molecularly characterized by the presence of the Philadelphia (Ph) chromosome, resulting from a (9;22)(q34;q11) reciprocal translocation. Expression of the resulting BCR-ABL1 oncogene is usually considered the initiating event in the genesis of this disease and is sufficient to induce leukemia. Thanks to its constitutively active tyrosine kinase activity, BCR-ABL1 is, indeed, able to mimic growth factors stimulation by activating many signaling pathways, leading to increased proliferation, decreased apoptosis, reduced growth factor-dependence, and abnormal interaction with extracellular matrix and stroma.Most CMLpatients are usually diagnosed in the initial, chronic phase of the disease and treated with first and/or second generation drugs designed to block the enzymatic activity of the BCR-ABL1tyrosine kinase, namely imatinib, dasatinib, and nilotinib. Still, approximately 20% of patients in chronic phase fail to respond to both imatinib and to subsequent second generation tyrosine kinase inhibitors (TKIs), with very poor prognosis once progressed to the advanced blastic phase. Therefore, while these TKIs have clearly revolutionized therapy for the disease, there is still need for supplementary or alternative options to “integrate” current pharmacological approaches. In this context, autophagy has been demonstrated as necessary for BCR-ABL1-induced leukemogenesis, as well as to protect cancer cells from apoptosis induced by antineoplastic drugs such as imatimib. Based on these evidences, an inhibitor of autophagy, hydroxychloroquine, has been already successfully used to potentiate TKI-induced cell death in Ph chromosome-positive cells, including primary CML stem cells. Importantly, new clinical trials are also investigating the effect of adding hydroxychloroquine to Imatinib treatment for CML (CHOICES trial, http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-hydroxychloroquine-with-imatinib-for-choices).MAPK15 is currently the last identified member of the MAP kinase family of proteins. Its activity can be modulated by nutrient deprivation, and by important human oncogenes, such as RET-PTC3, RET-MEN2B, and BCR-ABL1. Still, very limited information is available about the role of this MAP kinase in cell proliferation and transformation, sometimes with opposite results depending on the experimental system used. Indeed, while MAPK15 activity is important for transformation of humancolon cancer cells, its mouse orthologous gene negatively regulates cell growth of Cos7 cells. Importantly, we have recently described a role for MAPK15 in the regulation of autophagy, and have demonstrated the feasibility of pharmacologically interfering with this process by modulating the activity of this MAP kinase.Here, we show that BCR-ABL1 was able to modulate autophagy and that MAPK15 mediated this effect in an LIR-dependent manner. Moreover, not only artificial depletion of the endogenous MAP kinase inhibited BCR-ABL1-dependent autophagy but, also, we demonstrate that it was possible to pharmacologically interfere with this process by using a MAPK15 inhibitor. Importantly, based on the role of autophagy in BCR-ABL1-dependent transformation, we show that MAPK15 and its ability to control the autophagic process was required for cell proliferation and in vivo tumor development induced by this oncogene, therefore establishing MAPK15 as a novel potential and feasible therapeutic target for humanCML.
Results
BCR-ABL1 interacts with MAPK15 and colocalizes with it at phagophores
We have previously shown that the BCR-ABL1 oncogene stimulates MAPK15 activity and that the ABL1 proto-oncogene interacts with this MAP kinase and mediates its activation by RET-PTC3 (Fig. S1). Expanding these results, we therefore tested the interaction between MAPK15 and BCR-ABL1 and demonstrated that they readily coimmunoprecipitated (). In this context, sequence analysis of MAPK15 has already revealed the presence of 2 potential SH3-domain binding motifs, PXXP, within its C-terminal region and Abe and collaborators have demonstrated that such motifs associate with the SRC SH3 domain. We therefore tested whether MAPK15 could associate also with the ABL1 SH3 domain. To this aim, we cotransfected MAPK15 and an activated form of ABL1 (Act. ABL1) in which the SH3 domain has been deleted. In these settings, MAPK15 was still able to coimmunoprecipitate with the mutated protein, even in the absence of ABL1 SH3 (), suggesting the existence of additional domains in ABL1 able to mediate interaction with the MAP kinase.
Figure 1.
BCR-ABL1 interacts with MAPK15. (A) 293T cells were transfected with HA-MAPK15 and with plasmids encoding the empty vector or the indicated ABL1 and BCR-ABL1-expressing vectors. Total lysates were collected 24 h later and, after immunoprecipitation, western blot analysis was performed. Similar results were obtained in 3 independent experiments. (B) K562 cells were harvested and total lysates were collected. Lysates were subjected to immunoprecipitation with preimmune IgG, as control, or with anti-MAPK15 IgG. Then, immunoprecipitated protein complexes were analyzed by SDS-PAGE and western blot. Similar results were obtained in 3 independent experiments. (C) HeLa cells were transfected with HA-MAPK15 and BCR-ABL1 plasmids and then subjected to immunofluorescence analysis. MAPK15 is visualized in green, BCR-ABL1 in red, and DAPI-stained nuclei in blue. White arrows indicate colocalization spots. The Pearson correlation between MAPK15 and BCR-ABL1 was calculated (P = 0.658 ± 0 .071). The colocalization rate of MAPK15 and BCR-ABL1 was obtained by analyzing at least 400 cells from 3 different experiments (n = 3). Scale bars, 10 μm. (D) GFP-LC3 HeLa cells were transfected with HA-MAPK15 and BCR-ABL1 plasmids and then subjected to immunofluorescence analysis. GFP-LC3 is visualized in green, BCR-ABL1 in red, MAPK15 in cyan and DAPI-stained nuclei in blue. White arrows indicate colocalization spots. a, anti. Scale bars, 10 μm.
BCR-ABL1 interacts with MAPK15. (A) 293T cells were transfected with HA-MAPK15 and with plasmids encoding the empty vector or the indicated ABL1 and BCR-ABL1-expressing vectors. Total lysates were collected 24 h later and, after immunoprecipitation, western blot analysis was performed. Similar results were obtained in 3 independent experiments. (B) K562 cells were harvested and total lysates were collected. Lysates were subjected to immunoprecipitation with preimmune IgG, as control, or with anti-MAPK15 IgG. Then, immunoprecipitated protein complexes were analyzed by SDS-PAGE and western blot. Similar results were obtained in 3 independent experiments. (C) HeLa cells were transfected with HA-MAPK15 and BCR-ABL1 plasmids and then subjected to immunofluorescence analysis. MAPK15 is visualized in green, BCR-ABL1 in red, and DAPI-stained nuclei in blue. White arrows indicate colocalization spots. The Pearson correlation between MAPK15 and BCR-ABL1 was calculated (P = 0.658 ± 0 .071). The colocalization rate of MAPK15 and BCR-ABL1 was obtained by analyzing at least 400 cells from 3 different experiments (n = 3). Scale bars, 10 μm. (D) GFP-LC3HeLa cells were transfected with HA-MAPK15 and BCR-ABL1 plasmids and then subjected to immunofluorescence analysis. GFP-LC3 is visualized in green, BCR-ABL1 in red, MAPK15 in cyan and DAPI-stained nuclei in blue. White arrows indicate colocalization spots. a, anti. Scale bars, 10 μm.In order to define a physiological context for MAPK15 in BCR-ABL1 signaling, we analyzed a panel of myeloid and lymphoid cell lines for the expression of the MAP kinase (Fig. S2). Interestingly, all BCR-ABL1-encoding CML cell lines (KCL-22, LAMA84 and K562) expressed MAPK15 at high levels, whereas immortalized T lymphocyte cells (Jurkat) and other BCR-ABL1-negative leukemic cell lines (U937, REH and HL60) showed much lower MAPK15expression. Among BCR-ABL1 positive CML cell lines, exhibiting high levels of MAPK15, we then choose K562 cells to investigate the interaction between this kinase and BCR-ABL1, in their physiological context and at endogenous levels. In these conditions, BCR-ABL1 readily coimmunoprecipitated with endogenous MAPK15 (), which appeared as 2 bands possibly representing alternatively phosphorylated or cleaved forms of the protein.The BCR-ABL1 oncoprotein has been extensively localized to the cytoplasm and to the nucleus. In particular, BCR-ABL1 is restrained to the cytosol through its F-actin binding domain, but can translocate to the nucleus upon imatinib treatment, inducing cellular apoptosis. Therefore, we examined BCR-ABL1 and MAPK15 localization in our cellular model and demonstrated, by an immunofluorescence approach, that the 2 proteins colocalized with a very high Pearson correlation (P = 0.658 ± 0 .071, ), further supporting, in vivo, the evidence of their interaction. Interestingly, available data from cell fractionation and immunofluorescence experiments have shown that MAPK15, besides being localized to the cytoplasm and the nucleus, is also on vesicles identified as autophagic in nature. Remarkably, MAPK15 and BCR-ABL1 colocalization was also evident on intracellular vesicles (, confirming a punctate pattern already described for BCR-ABL1. We, therefore, took advantage of HeLa cells stably expressing GFP-LC3B to investigate the localization of both these molecules on autophagic vesicles and confirmed their colocalization with LC3B, a marker of phagophores and autophagosomes (). Altogether, our data demonstrate physical interaction, at the endogenous levels, of the BCR-ABL1 oncoprotein with MAPK15, on vesicles of autophagic origin, suggesting their interplay as functionally important to control oncogene-dependent functions.
BCR-ABL1 induces autophagy
Some data indicate that BCR-ABL1 is involved in the regulation of autophagy in leukemic cells. However, its precise role in this process is still the object of controversy. Indeed, on one hand imatinib, the most used BCR-ABL1 inhibitor, has been described to increase autophagy in leukemic cells, suggesting this oncogene as a negative regulator of autophagy whereas, on the other hand, it has been demonstrated that BCR-ABL1 cellular transformation is dependent on autophagy for cancer cell survival and proliferation. In this context, we decided to examine BCR-ABL1 effect in a well-established model for the study of autophagy, i.e. the HeLa cancer cell line. To this aim, we created an inducible cell line for BCR-ABL1, HeLa-T-Rex-BCR-ABL1, in order to circumvent potential biases arising from stress induced by transient transfection. In this cellular system, BCR-ABL1 was expressed only upon doxycycline treatment (). Next, we analyzed the effect of BCR-ABL1expression on autophagy, by monitoring the average number of autophagosomes per cell. In HeLa-T-Rex-BCR-ABL1 cells, the expression of the oncogenic fusion protein led to a significant increase in the amount of LC3B dots per cell, compared to control sample (). In order to confirm these data, we also examined the autophagic flux in HeLa cell by analyzing the amount of the lipidated, autophagosome-associated form of LC3B (LC3B-II) in cells treated with an inhibitor of lysosomal proteases, bafilomycin A1 (Baf). Indeed, induction of autophagy is associated to an increase of LC3B-II that can be monitored by using anti-LC3B antibodies specifically recognizing this modified protein. As shown in , BCR-ABL1 increased the amount of LC3B-II in HeLa cells when compared to control samples. Moreover, to specifically determine the autophagic flux, BCR-ABL1-expressing cells were treated with Baf, revealing a further increase in LC3B-II amount when compared to untreated controls. Thus, the BCR-ABL1 oncoprotein led to an increase of autophagic flux in HeLa cells, indicating that BCR-ABL1 is a positive regulator of autophagy. As a further control, we also overexpressed a dominant negative construct encoding for a kinase dead ABL1 isoform. Unlike BCR-ABL1, this construct caused a reduction of the autophagic flux compared to control samples (), indicating that tyrosine kinase activity is implicated in BCR-ABL1-dependent regulation of autophagy. Taken together, these data suggested that BCR-ABL1 is a bona fide inducer of the autophagic process.
Figure 2.
BCR-ABL1 induces autophagy in HeLa cells. (A) HeLa T-Rex BCR-ABL1 cells were treated with doxycycline for the indicated periods. Then, total lysates were collected and subjected to western blot analysis. Similar results were obtained in 3 independent experiments. (B) HeLa T-Rex BCR-ABL1 cells were treated with doxycycline for 24 h. Cells were stained for LC3B with a specific antibody, in green, and with DAPI for nuclei, in blue. LC3B-positive dots were counted using a specific protocol by Volocity software (see graph on the right). Similar results were obtained in 3 independent experiments (n = 3). Scale bars, 10 μm. (C) HeLa cells were transfected with HA-MAPK15, BCR-ABL, GFP-ABLKD or control plasmids. After 24 h, cells were treated with 100 nM Baf for 1 h and total lysates were collected for western blotting analysis. Densitometric analysis of bands was also performed on this experiment, representative of 3 independent experiments (n = 3).
BCR-ABL1 induces autophagy in HeLa cells. (A) HeLa T-RexBCR-ABL1 cells were treated with doxycycline for the indicated periods. Then, total lysates were collected and subjected to western blot analysis. Similar results were obtained in 3 independent experiments. (B) HeLa T-RexBCR-ABL1 cells were treated with doxycycline for 24 h. Cells were stained for LC3B with a specific antibody, in green, and with DAPI for nuclei, in blue. LC3B-positive dots were counted using a specific protocol by Volocity software (see graph on the right). Similar results were obtained in 3 independent experiments (n = 3). Scale bars, 10 μm. (C) HeLa cells were transfected with HA-MAPK15, BCR-ABL, GFP-ABLKD or control plasmids. After 24 h, cells were treated with 100 nM Baf for 1 h and total lysates were collected for western blotting analysis. Densitometric analysis of bands was also performed on this experiment, representative of 3 independent experiments (n = 3).
MAPK15 mediates BCR-ABL1-induced autophagy
We have recently described MAPK15 as a regulator of the autophagic process. As BCR-ABL1 was able to induce autophagy, to stimulate MAPK15 activity, and to interact with this MAP kinase (see above), we decided to examine whether MAPK15 was able to modulate BCR-ABL1-induced autophagy. We therefore exploited a RNA interference approach, by using already validated commercial MAPK15-specific siRNAs, custom-made siRNAs (Fig. S3), and commercial shRNAs (Fig. S4), in HeLa cells expressing BCR-ABL1. In these settings, using MAPK15 siRNAs, we observed a significant decrease in the number of autophagosomes in BCR-ABL1-expressing cells depleted for MAPK15, comparing with those treated with control siRNA (). Furthermore, we also assessed the autophagic activity of cells stably expressing BCR-ABL1 and MAPK15-specific shRNAs, by monitoring LC3B and SQSTM1 protein levels under full medium, starvation, and Baf treatment conditions. As expected, interfering with MAPK15expression strongly reduced autophagic flux and starvation-induced autophagy (). BCR-ABL1, when expressed, stimulated the autophagic flux, whereas depletion of MAPK15 in BCR-ABL1-expressing cells caused a reduction in this flux and a decrease in the starvation-induced autophagic response (). Once established that MAPK15 controlled BCR-ABL1-induced autophagy in HeLa model cell lines, we next sought to confirm the existence of this specific pathway in K562CML cells endogenously expressing both these kinases (see above). Autophagic flux was, therefore, evaluated by western blot in K562 cells, comparing shSCR with shMAPK15. MAPK15-depleted K562 cells had, indeed, a decreased autophagic flux with a higher basal level for SQSTM1 and a reduced increase for LC3B-II upon Baf treatment (). To corroborate this data, we also evaluated autophagy by immunofluorescence, using specific shRNA for MAPK15 in K562 cells, demonstrating a strong reduction in the amount of autophagic vesicles per cell, in both basal conditions and upon Baf treatment (Fig.4B). Altogether these data further confirm that BCR-ABL1 was able to induce autophagy and that MAPK15 was important for proper basal autophagic response, while ultimately demonstrating a role for this endogenous MAP kinase in mediating BCR-ABL1-induced autophagy.
Figure 3.
MAPK15 mediates BCR-ABL1-induced autophagy. (A) HeLa T-Rex BCR-ABL1 cells were transfected with scrambled or MAPK15 siRNA. After 48 h cells were treated with doxycycline for 24 h and subjected to immunofluorescence analysis. In these representative images, LC3B is visualized in green and DAPI-stained nuclei in blue. LC3B-positive dots were counted using a specific protocol by Volocity software (see graph on the right). Scale bars, 25 μm. (B) HeLa cells, stable for the indicated plasmids (empty vector, BCR-ABL1, shSCR or shMAPK15), were treated as indicated: starvation was performed in Hank's medium for 20 min, 100 nM Baf was added for 1 h. Then, total lysates were harvested and subjected to western blot analysis. One experiment, representative of 3 independent experiments is shown (n = 3). Densitometric analysis of bands was also performed.
Figure 4.
MAPK15 mediates BCR-ABL1-induced autophagy in CML cells. (A) K562 cells, stably expressing the indicated plasmids (shSCR or shMAPK15), were treated as indicated: 100 nM WM or 100 nM Baf was added for 1 h. Then, total lysates were harvested and subjected to western blot analysis. One experiment, representative of 3 independent experiments is shown (n = 3). Densitometric analysis of bands was also performed. (B) K562 cells, stably expressing the indicated plasmids (shSCR or shMAPK15), were treated with 100 nM Baf (1 h), and then cells were subjected to immunofluorescence analysis. In these representative images, LC3B is visualized in green and DAPI-stained nuclei in blue. LC3B positive dots were counted using a specific protocol by Volocity software (see graph on the right). Scale bars, 7.5 μm.
MAPK15 mediates BCR-ABL1-induced autophagy. (A) HeLa T-RexBCR-ABL1 cells were transfected with scrambled or MAPK15 siRNA. After 48 h cells were treated with doxycycline for 24 h and subjected to immunofluorescence analysis. In these representative images, LC3B is visualized in green and DAPI-stained nuclei in blue. LC3B-positive dots were counted using a specific protocol by Volocity software (see graph on the right). Scale bars, 25 μm. (B) HeLa cells, stable for the indicated plasmids (empty vector, BCR-ABL1, shSCR or shMAPK15), were treated as indicated: starvation was performed in Hank's medium for 20 min, 100 nM Baf was added for 1 h. Then, total lysates were harvested and subjected to western blot analysis. One experiment, representative of 3 independent experiments is shown (n = 3). Densitometric analysis of bands was also performed.MAPK15 mediates BCR-ABL1-induced autophagy in CML cells. (A) K562 cells, stably expressing the indicated plasmids (shSCR or shMAPK15), were treated as indicated: 100 nM WM or 100 nM Baf was added for 1 h. Then, total lysates were harvested and subjected to western blot analysis. One experiment, representative of 3 independent experiments is shown (n = 3). Densitometric analysis of bands was also performed. (B) K562 cells, stably expressing the indicated plasmids (shSCR or shMAPK15), were treated with 100 nM Baf (1 h), and then cells were subjected to immunofluorescence analysis. In these representative images, LC3B is visualized in green and DAPI-stained nuclei in blue. LC3B positive dots were counted using a specific protocol by Volocity software (see graph on the right). Scale bars, 7.5 μm.
Localization of BCR-ABL1 to autophagic vesicles is mediated by the ability of MAPK15 to interact with LC3-family proteins, in an LIR-dependent manner
Since MAPK15 is localized to autophagic vesicles thanks to LC3-interacting region (LIR)-dependent interactions, we investigated whether this domain was also necessary for BCR-ABL1 localization to autophagic vesicles. Indeed, BCR-ABL1 colocalized with LC3B-positive dots in cells expressing wild-type (WT) MAPK15 (), whereas no localization of BCR-ABL1 was observed in cells expressing a LIR-defective MAPK15 mutant (MAPK15AXXA; ). To confirm the formation of a complex between BCR-ABL1 and LC3B, mediated by MAPK15 and its LIR motif, we next precipitated a GST-fused BCR-ABL1 isoform by affinity purification together with WT and LIR-defective MAPK15 and evaluated endogenous LC3B coprecipitation. Interestingly, BCR-ABL1 was able to precipitate LC3B only in presence of WT MAPK15 whereas the expression of the MAPK15AXXA mutant completely prevented LC3 precipitation by BCR-ABL1 (
and Fig. S5). Based on these results, we also investigated whether correct localization of BCR-ABL1 to autophagic vesicles was required for oncoprotein-induced autophagy. Hence, we evaluated autophagic flux and autophagosome amount in WT MAPK15- and MAPK15AXXA-expressing cells. These experiments highlighted the ability of the MAPK15 LIR mutant, which prevented BCR-ABL1 relocalization on autophagic vesicles, to strongly inhibit BCR-ABL1-induced autophagy and autophagic flux, as scored by accumulation of LC3B-II protein () and by the decreased number of autophagosomes (). Altogether, these data demonstrated that BCR-ABL1 is localized on autophagic vesicles by MAPK15-dependent interaction with LC3B and that such localization is required for BCR-ABL1 induction of autophagy.
Figure 5.
Localization of BCR-ABL1 to autophagic vesicles is mediated by the ability of MAPK15 to interact with LC3-family proteins, in an LIR-dependent manner. (A-B) GFP-LC3B HeLa cells were transfected with BCR-ABL1 and WT HA-MAPK15 or HA-MAPK15AXXA plasmids and then subjected to immunofluorescence analysis. GFP-LC3 is visualized in green, BCR-ABL1 in red, MAPK15 in cyan, and DAPI-stained nuclei in blue. In these representative images, white arrows indicate colocalization spots. Scale bars, 10 μm. (C) 293T cells were transfected with the indicated plasmids (empty vector, GST, GST-BCR-ABL, BCR-ABL, WT HA-MAPK15 or HA-MAPK15AXXA) and harvested after 24 h. Total lysates were then subjected to GST affinity purification and analyzed by western blot. Similar results were obtained in 3 independent experiments (n = 3). (D) HeLa cells were transfected with BCR-ABL1, WT HA-MAPK15, HA-MAPK15AXXA or control plasmids. After 24 h, cells were treated with 100 nM Baf for 1 h and total lysates were harvested for western blotting analysis. One experiment, representative of 3 independent experiments is shown. Densitometric analysis of bands was also performed. (E) GFP-LC3B Hela cells were transfected with BCR-ABL, HA-MAPK15AXXA or control plasmids. After 48 h, cells were treated with 100 nM Baf for 1 h and fixed. Then cells were immunolabeled for BCR-ABL1 and MAPK15. Positive cells for BCR-ABL1, MAPK15 or both were then analyzed for the number of LC3B dots using a specific protocol by Volocity software. The accompanying histogram was obtained by analyzing at least 400 cells/sample from 3 different experiments (n = 3).
Localization of BCR-ABL1 to autophagic vesicles is mediated by the ability of MAPK15 to interact with LC3-family proteins, in an LIR-dependent manner. (A-B) GFP-LC3B HeLa cells were transfected with BCR-ABL1 and WT HA-MAPK15 or HA-MAPK15AXXA plasmids and then subjected to immunofluorescence analysis. GFP-LC3 is visualized in green, BCR-ABL1 in red, MAPK15 in cyan, and DAPI-stained nuclei in blue. In these representative images, white arrows indicate colocalization spots. Scale bars, 10 μm. (C) 293T cells were transfected with the indicated plasmids (empty vector, GST, GST-BCR-ABL, BCR-ABL, WT HA-MAPK15 or HA-MAPK15AXXA) and harvested after 24 h. Total lysates were then subjected to GST affinity purification and analyzed by western blot. Similar results were obtained in 3 independent experiments (n = 3). (D) HeLa cells were transfected with BCR-ABL1, WT HA-MAPK15, HA-MAPK15AXXA or control plasmids. After 24 h, cells were treated with 100 nM Baf for 1 h and total lysates were harvested for western blotting analysis. One experiment, representative of 3 independent experiments is shown. Densitometric analysis of bands was also performed. (E) GFP-LC3B Hela cells were transfected with BCR-ABL, HA-MAPK15AXXA or control plasmids. After 48 h, cells were treated with 100 nM Baf for 1 h and fixed. Then cells were immunolabeled for BCR-ABL1 and MAPK15. Positive cells for BCR-ABL1, MAPK15 or both were then analyzed for the number of LC3B dots using a specific protocol by Volocity software. The accompanying histogram was obtained by analyzing at least 400 cells/sample from 3 different experiments (n = 3).
MAPK15 catalytic activity is required for BCR-ABL1-dependent induction of autophagy
Over the past decade, protein kinases have become the pharmaceutical industry’s most popular drug targets, especially in the field of cancer. Consequently, based on the potential role of MAPK15 in autophagy and cancer, we decided to investigate whether its enzymatic activity was required for BCR-ABL1-induced autophagy. Thus, we overexpressed the kinase inactive mutant of MAPK15 (MAPK15KD, Asp154Ala (D154A) mutation) in BCR-ABL1-positive cells and monitored the expression levels of autophagic markers such as LC3-II and SQSTM1. In these settings, the MAPK15KD mutant reduced both basal and BCR-ABL1-induced autophagy (). A further control of autophagy constraint by MAPK15KD came from analysis of the autophagic flux. Indeed, this analysis evidenced that this mutant reduced flux of both basal and BCR-ABL1-induced autophagy (). Moreover, we monitored autophagy in BCR-ABL1-expressing cells treated with the MAPK15 kinase inhibitor, Ro318220. Also in this case, inhibition of MAPK15 catalytic activity led to a reduction of BCR-ABL1-induced autophagy () and autophagic flux of both basal and BCR-ABL1-induced autophagy (). Altogether, these data indicate that MAPK15 kinase activity is necessary to mediate BCR-ABL1-dependent autophagy.
Figure 6.
MAPK15 catalytic activity is required for BCR-ABL1-dependent induction of autophagy. (A) HeLa cells were transfected with BCR-ABL1 and HA-MAPK15KD plasmids. After 24 h, total lysates were collected for western blotting analysis. Representative western blot shows levels of the LC3B and SQSTM1 autophagic markers in cells expressing BCR-ABL1 with or without MAPK15KD. Densitometric analysis of bands was also performed. Histograms show means ± SD of densitometric analysis for LC3B-II, SQSTM1 and MAPK1 from 3 independent experiments (n = 3). (B) HeLa cells were transfected with BCR-ABL1, HA-MAPK15KD or control plasmids. After 24 h, cells were treated with 100 nM Baf for 1 h and total lysates were harvested for western blotting analysis. One experiment, representative of 3 independent experiments is shown (n = 3). Densitometric analysis of bands was also performed. (C) HeLa cells were transfected with BCR-ABL1 or control plasmids. After 24 h, cells were treated with 1uM Ro318220 for 1 h and total lysates were collected for western blotting analysis. Similar results were obtained in 3 independent experiments. Densitometric analysis of bands was also performed. Charts show means ± SD of densitometric analysis for LC3B-II, SQSTM1, and MAPK1 from 3 independent experiments (n = 3). (D) HeLa cells were transfected with BCR-ABL1 or control plasmids. After 24 h, cells were treated with 1uM Ro318220 and 100 nM Baf for 1 h, as indicated, and total lysates were harvested for western blotting analysis. Similar results were obtained in 3 independent experiments (n = 3). Densitometric analysis of bands was also performed.
MAPK15 catalytic activity is required for BCR-ABL1-dependent induction of autophagy. (A) HeLa cells were transfected with BCR-ABL1 and HA-MAPK15KD plasmids. After 24 h, total lysates were collected for western blotting analysis. Representative western blot shows levels of the LC3B and SQSTM1 autophagic markers in cells expressing BCR-ABL1 with or without MAPK15KD. Densitometric analysis of bands was also performed. Histograms show means ± SD of densitometric analysis for LC3B-II, SQSTM1 and MAPK1 from 3 independent experiments (n = 3). (B) HeLa cells were transfected with BCR-ABL1, HA-MAPK15KD or control plasmids. After 24 h, cells were treated with 100 nM Baf for 1 h and total lysates were harvested for western blotting analysis. One experiment, representative of 3 independent experiments is shown (n = 3). Densitometric analysis of bands was also performed. (C) HeLa cells were transfected with BCR-ABL1 or control plasmids. After 24 h, cells were treated with 1uM Ro318220 for 1 h and total lysates were collected for western blotting analysis. Similar results were obtained in 3 independent experiments. Densitometric analysis of bands was also performed. Charts show means ± SD of densitometric analysis for LC3B-II, SQSTM1, and MAPK1 from 3 independent experiments (n = 3). (D) HeLa cells were transfected with BCR-ABL1 or control plasmids. After 24 h, cells were treated with 1uM Ro318220 and 100 nM Baf for 1 h, as indicated, and total lysates were harvested for western blotting analysis. Similar results were obtained in 3 independent experiments (n = 3). Densitometric analysis of bands was also performed.
MAPK15 depletion inhibits BCR-ABL1-dependent cell proliferation and in vivo tumor formation
BCR-ABL1expression confers cells the ability to proliferate in the absence of growth signals and to escape apoptosis. Indeed, we confirmed the ability of this oncogene to increase proliferation also in our model system, HeLa cells (Fig. S6). Based on the role of MAPK15 in autophagy induced by BCR-ABL1 and on the already demonstrated role of this cellular process in cell survival and leukemogenesis controlled by this oncogene, we next asked whether MAPK15 may have a role in BCR-ABL1-dependent cell proliferation. Using a MAPK15 depletion approach (see above), we indeed demonstrated that interfering for the expression of the endogenous MAP kinase caused a significant reduction in HeLa cell proliferation induced by BCR-ABL1 overexpression (), without affecting apoptosis in these cells (Fig. S7).
Figure 7.
MAPK15 depletion inhibits BCR-ABL1-dependent cell proliferation and transformation. (A) HeLa cells were transfected with SCR siRNA or MAPK15 specific siRNA. After 8 h cells were transfected with BCR-ABL1 or control plasmids. After further 64 h, cells were harvested and counted. (B) HeLa cells were transfected with SCR siRNA or MAPK15 specific siRNA. After 24 h cells were transfected with BCR-ABL1 or control plasmids. Cells were then assessed for anchorage-independent growth by seeding them into agar medium. After 14 d, colonies were counted. All quantitative data shown represent the means ± SD of 3 independent experiments (n = 3). (C) K562 cells, stable for the indicated shRNA-encoding plasmids, were seeded in 6-well plates at 2 × 105 cells per well in triplicate. After 72 h, cells were harvested and counted. One-way ANOVA test comparing each shSCR cell line with each shMAPK15 cell line resulted in a P value significance lower than 0.001 (***). (D) Growth curves of tumors generated by K562 cells stably expressing 2 independent shRNA SCR (#509 and #543) and 2 independent shRNA for MAPK15 (#547 and #549), after injection on the flank of athymic nude-FOXN1nu mice. Each point represents the mean volume ± SEM of 10 tumors. One-way ANOVA test for tumor volume at time points of 13, 16, 19 d comparing each shSCR xenograft group with each shMAPK15 xenograft group resulted in a P value significance lower than 0.001 (***).
MAPK15 depletion inhibits BCR-ABL1-dependent cell proliferation and transformation. (A) HeLa cells were transfected with SCR siRNA or MAPK15 specific siRNA. After 8 h cells were transfected with BCR-ABL1 or control plasmids. After further 64 h, cells were harvested and counted. (B) HeLa cells were transfected with SCR siRNA or MAPK15 specific siRNA. After 24 h cells were transfected with BCR-ABL1 or control plasmids. Cells were then assessed for anchorage-independent growth by seeding them into agar medium. After 14 d, colonies were counted. All quantitative data shown represent the means ± SD of 3 independent experiments (n = 3). (C) K562 cells, stable for the indicated shRNA-encoding plasmids, were seeded in 6-well plates at 2 × 105 cells per well in triplicate. After 72 h, cells were harvested and counted. One-way ANOVA test comparing each shSCR cell line with each shMAPK15 cell line resulted in a P value significance lower than 0.001 (***). (D) Growth curves of tumors generated by K562 cells stably expressing 2 independent shRNA SCR (#509 and #543) and 2 independent shRNA for MAPK15 (#547 and #549), after injection on the flank of athymic nude-FOXN1nu mice. Each point represents the mean volume ± SEM of 10 tumors. One-way ANOVA test for tumor volume at time points of 13, 16, 19 d comparing each shSCR xenograft group with each shMAPK15 xenograft group resulted in a P value significance lower than 0.001 (***).Neoplastic transformation occurs via a series of genetic and epigenetic alterations that give rise to a cell population capable of proliferating independently of both external and internal signals. Anchorage-independent growth is one of the hallmarks of cell transformation and in vitro assays monitoring this phenomenon are considered among the most accurate and stringent for detecting malignant transformation of cells. Indeed, we performed soft-agar assays with HeLa cells overexpressing BCR-ABL1 and, demonstrated that the oncogene increased the number of transformed colonies (Fig. S8). To establish a role for MAPK15 in BCR-ABL1-dependent cellular transformation, we therefore evaluated colony formation ability demonstrating that MAPK15 depletion caused a reduction in the number of anchorage-independent colonies from BCR-ABL1-expressing cells ().To confirm that MAPK15 is necessary for BCR-ABL1 biological effects in a system expressing this oncogene at physiologically relevant levels, we next evaluated cell proliferation of K562CML cells depleted for MAPK15expression. Indeed, K562 cells expressing 2 different MAPK15 specific shRNA (#547 and #549) showed significantly reduced proliferation rates as compared to K562 cells expressing 2 independent control shRNAs (scrambled, SCR, #509 and #543) ().Ultimately, K562-dependent tumor formation was assessed, in vivo, by a xenograft approach in nude mice. Two lines for K562 expressing control shRNAs (SCR, #509 and #543) and 2 for K562 cells expressing MAPK15 specific shRNAs (#547 and #549) were inoculated in athymic nude-FOXN1nu/nu mice and tumor growth was monitored over a time span of approximately 3 wk. Tumor growth rates in the 4 experimental groups significantly diverged early on during the period of observation, with most of the inoculi generated with MAPK15-depleted K562 cells being completely unable to form appreciable tumors at the endpoint of the experiment (). Overall, our data therefore demonstrated a key role of the endogenous MAPK15 protein in mediating BCR-ABL1-dependent transformation signals, both in a model system (HeLa cells) exogenously expressing BCR-ABL1 and in a physiologically relevant model for CML, i.e. K562 cells endogenously expressing the BCR-ABL1human oncogene.
MAPK15-dependent regulation of autophagy is necessary for BCR-ABL1-dependent cell proliferation and tumor formation
Based on previously described results, we finally aimed at demonstrating that MAPK15-dependent autophagy was indeed crucial for BCR-ABL1-dependent cell proliferation and tumor formation in K562 cells, in which a pharmacological inhibitor of autophagy, chloroquine, has already been demonstrated to inhibit cell proliferation even when associated to low doses of imatinib. For this, we took advantage of the previously described LIR-defective and autophagy-incompetent MAPK15AXXA mutant, that nonetheless maintains its kinase activity. We, therefore, generated K562 cells stably expressing this mutant and, as additional controls, an empty vector, WT MAPK15 and a MAPK15 kinase dead mutant (MAPK15KD). Their proliferation rate was evaluated by Trypan blue exclusion assay, demonstrating that both the MAPK15AXXA and the MAPK15KD mutants caused, respectively, a 43% and 58% decrease in cell amount compared to WT MAPK15 ().
Figure 8.
MAPK15-dependent autophagy controls BCR-ABL1-dependent cell proliferation and tumor formation. (A) K562 cells stably expressing empty vector, WT MAPK15, MAPK15AXXA and MAPK15KD were seeded in 6-well plates at 2 × 105 cells per well in triplicate. After 72 h, cells were harvested and counted. (B) Growth curves of tumors generated by K562 cells stably expressing empty vector, WT MAPK15, MAPK15AXXA and MAPK15KD, after injection on the flank of athymic nude-FOXN1nu mice. Each point represents the mean volume ± SEM of 10 tumors. One-way ANOVA test for tumor volume at time points of 17 and 21 d comparing each MAPK15 mutant xenograft group (MAPK15AXXA and MAPK15KD) with WT MAPK15 xenograft group resulted in a P value significance lower than 0.001 (***).
MAPK15-dependent autophagy controls BCR-ABL1-dependent cell proliferation and tumor formation. (A) K562 cells stably expressing empty vector, WT MAPK15, MAPK15AXXA and MAPK15KD were seeded in 6-well plates at 2 × 105 cells per well in triplicate. After 72 h, cells were harvested and counted. (B) Growth curves of tumors generated by K562 cells stably expressing empty vector, WT MAPK15, MAPK15AXXA and MAPK15KD, after injection on the flank of athymic nude-FOXN1nu mice. Each point represents the mean volume ± SEM of 10 tumors. One-way ANOVA test for tumor volume at time points of 17 and 21 d comparing each MAPK15 mutant xenograft group (MAPK15AXXA and MAPK15KD) with WT MAPK15 xenograft group resulted in a P value significance lower than 0.001 (***).Ultimately, to evaluate the role of autophagy controlled by MAPK15 in endogenous BCR-ABL1-dependent in vivo tumor formation, we injected K562 cells stably expressing empty vector and WT, AXXA, and KD MAPK15 mutants, in athymic nude-FOXN1nu/nu mice and monitored their tumor growth over a time span of 3 wk. At the endpoint of observations, the MAPK15AXXA mutant (with impaired autophagic activity) and the MAPK15KD (with impaired kinase and autophagic activity) mutant significantly affected K562-dependent tumor growth, as compared to WT MAPK15 (). Altogether these data, therefore, demonstrated that the ability of MAPK15 to control the autophagic process is necessary for mediating BCR-ABL1-dependent oncogenic effects. Importantly, they also confirm that targeting MAPK15 kinase activity impairs the oncogenic potential of BCR-ABL1 in CML cells suggesting this MAP kinase as a novel pharmacological target for the therapy of humanCML.
Discussion
Autophagy has been demonstrated as necessary for BCR-ABL1-induced leukemogenesis. In this study, we show that MAPK15 mediated BCR-ABL1-induced autophagy and that this signaling pathway is necessary for proliferation and transformation sustained by this human oncogene (). At the molecular level, BCR-ABL1 interacted with and activated MAPK15 and their binding promoted BCR-ABL1 relocalization to autophagic vesicles. Furthermore, MAPK15 depletion or pharmacological inhibition limited BCR-ABL1-induced autophagy, supporting the possibility that specific MAPK15 inhibitors may be beneficial for the therapy of humanCML. Although, at the moment, we have no experimental evidence sustaining a similar role for this MAP kinase in controlling autophagy by other human oncogenes, available data from our laboratory suggest that MAPK15 mediates activation of autophagy also by starvation, while rapamycin, another typical stimulus, seems not to affect its activity. Our hypothesis is, therefore, that MAPK15 will likely transduce autophagy signals by other stimuli, possibly oncogenes, and we are currently investigating this issue for its potentially general importance on cellular transformation and humancancer.
Figure 9.
MAPK15 mediates BCR-ABL1-induced autophagy and cellular transformation. (A) BCR-ABL1 interacts with MAPK15 inducing autophagy, resulting in cell proliferation and transformation. (B) In cells depleted for MAPK15 expression or kinase activity (or even expressing a LIR-deficient mutant, MAPK15AXXA), BCR-ABL1 is unable to trigger autophagy, cell proliferation, and transformation.
MAPK15 mediates BCR-ABL1-induced autophagy and cellular transformation. (A) BCR-ABL1 interacts with MAPK15 inducing autophagy, resulting in cell proliferation and transformation. (B) In cells depleted for MAPK15expression or kinase activity (or even expressing a LIR-deficient mutant, MAPK15AXXA), BCR-ABL1 is unable to trigger autophagy, cell proliferation, and transformation.It is interesting to notice that all BCR-ABL1-expressing CML cell lines analyzed expressed MAPK15 at very high levels, whereas immortalized T lymphocyte cells and other BCR-ABL1 negative leukemic cells showed much lower MAPK15expression (Fig. S2). A possible explanation for this result is that the BCR-ABL1 oncogene itself is able to control MAPK15expression, which, in turn, actively participates in the leukemogenic process, thanks to its ability to control autophagy, as demonstrated in this report. Moreover, besides BCR-ABL1, other human oncogenes with constitutive tyrosine kinase activity have been reported to control MAPK15 activity, while no data is currently available regarding the ability of these oncogenes to control its expression. Still, as this MAP kinase is devoid of upstream MEKs (ref. 22 and our observations), and it can be controlled at the level of expression and/or stability by different stimuli, we are now actively pursuing the idea that expression of the kinase is under the control of specific oncogenic signaling pathways that are, in turn, able to take advantage of MAPK15 ability to stimulate autophagy and, consequently, cell proliferation, and tumor formation.Interestingly, the BCR-ABL1 oncoprotein has been extensively localized to the cytoplasm and to the nucleus, although only recently an F-actin binding domain in BCR-ABL1 has been identified and its localization on the cytoskeleton has been intensely investigated. Simple disruption of the BCR-ABL1 F-actin binding domain causes loss of cytoskeletal distribution and relocalization to cytoplasmatic puncta of BCR-ABL1. A similar distribution of BCR-ABL1 has been also shown in leukemic cells upon chemotherapeutic treatment, and such BCR-ABL1 cytoplasmic dots have been recognized as autophagosomes. Here, we confirm that BCR-ABL1 is localized on autophagic vesicles by demonstrating its colocalization with 2 previously described markers, MAPK15 and LC3B. In addition, we also established that BCR-ABL1 localization to autophagic vesicles is dependent on its interaction with MAPK15 and on the presence, in MAPK15, of an intact LIR motif. Indeed, overexpression of a LIR-defective mutant of MAPK15 prevented BCR-ABL1 localization to LC3B-positive structures. It is therefore tempting to speculate that MAPK15, while transducing signals upon BCR-ABL1 activation, may also be important for specific localization of this oncoprotein and, possibly, of the wild-type ABL1 protein, on autophagic vesicles. This, in turn, might allow BCR-ABL1 to access specific sets of autophagic vesicle-localized proteins, strongly sustaining the recent interest in autophagy for the treatment of CML.While the role of autophagy in BCR-ABL1-dependent leukemogenesis is now established, the molecular mechanisms by which the leukemic driver controls this process are still mostly unclear. In particular, few papers adopt genetic approaches to investigate the direct effect of BCR-ABL1 on autophagy and try to dissect downstream signals to the autophagic process. Conversely, here we show that ectopic addition of the BCR-ABL1 oncogene could affect cell autophagic rates ( and ) and that depletion of endogenous MAPK15 inhibits this effect, even in a physiologically relevant system in which the oncogene is endogenously expressed. Interestingly, the use of a MAPK15 mutant specifically devoid of a LIR domain necessary for autophagy regulation but still proficient for kinase activity, strongly interfered with the ability of BCR-ABL1 i) to stimulate autophagy, ii) to localize to autophagic vesicles, iii) to stimulate cell proliferation and, iv) to sustain tumor formation in vivo, supporting a key role of MAPK15-dependent autophagy in CML. Importantly, our data confirm previous observations describing leukemogenesis as a process highly dependent on autophagy. Altogether, our hypothesis is that BCR-ABL1 encodes for a constitutive active tyrosine kinase that controls the autophagic process in a MAPK15-dependent fashion, lowering cell stress and allowing leukemogenesis. Based on this, we predict that inhibition of autophagy by pharmacologically acting on MAPK15 might have therapeutic effects on CML, in association with specific BCR-ABL1 kinase inhibitors. In this context, the identification of MAPK15 as a new target for the development of small drug inhibitors, able to affect CML through regulation of the autophagic process elicited by BCR-ABL1, surely deserves attention and further investigation.
Materials and Methods
Reagents and antibodies
Bafilomycin A1 (Baf) (Santa Cruz Biotechnology, sc-201550) and Ro318220 (VWR International, 557521–500) were dissolved in DMSO. Hank's medium (H15–010), used as starvation medium, was obtained by PAA. The following primary antibody was used for immunoprecipitations: anti-HA (Covance, MMS-101R). For western blots, the following primary antibodies were used: anti-MAPK15 (custom preparation), anti-HA (Covance, MMS-101R), anti-LC3B (Nanotools, 0231–1000), anti-phospho-MAPK1/3 (Thr202/Tyr204) (Cell Signaling Technology, 9101), anti-SQSTM1/p62 (BD Biosciences, 610833), anti-ABL1 (BD Pharmingen, 554148) anti-MAPK1 (Santa Cruz Biotechnology, sc-154). For confocal microscopy experiments, the following primary antibodies were used: anti-MAPK15 (custom preparation), anti-HA (Santa Cruz Biotechnology, sc-7392), anti-LC3B (MBL, M152–3), anti-ABL1 (BD PharMingen, 554148), anti-ABL1 (Santa Cruz Biotechnology, sc-131). The following secondary antibodies were used for western blot experiments: anti-mouse (Santa Cruz Biotechnology, sc-2004) and anti-rabbit (Santa Cruz Biotechnology, sc-2005) HRP-conjugated IgGs. The following secondary antibodies were used for confocal microscopy experiments: anti-mouseAlexa Fluor 488-conjugated (Life Technologies, A21202), anti-rabbitAlexa Fluor 488-conjugated (Life Technologies, A21206), anti-mouseAlexa Fluor 555-conjugated (Life Technologies, A31570), anti-rabbitAlexa Fluor 555-conjugated (Life Technologies, A31572), anti-mouseAlexa Fluor 647-conjugated (Life Technologies, A31571), anti-rabbitAlexa Fluor 647-conjugated (Life Technologies, A31573).
Expression vectors
pCEFL-HA-MAPK15 and all its mutants have already been described. ABL1 encoding plasmids: pCEFL-c-ABL1, pCEFL-EGFP-ABL1, pCEFL-ABL1KD (kinase dead), pCEFL-BCR-ABL1 are already described. pcDNA4-Tet-On-BCR-ABL1 was generated by subcloning with EcoRI restriction sites the BCR-ABL1 gene from the MIG-210 BCR-ABL1 plasmid, kindly provided from Ricardo Sanchez Prieto (Universidad de Castilla-La Mancha), into the pcDNA4 Tet-inducible vector, kindly provided from Francesca Carlomagno (Università degli Studi di Napoli). The plasmid encoding for GST-tagged isoform of BCR-ABL1, pLEF GST-BCR-ABL1(p210) was obtained from Addgene (plasmid 38158, deposited by Nora Heisterkamp). pCEFL-EGFP-LC3B is already described. pGIPZ plasmids encoding for shRNA scrambled and shRNA MAPK15 were purchased from Open Biosystem (RHS4531-EG225689). pCEFL-MAPK15-IRES-GFP and all its mutants (AXXA; KD) were generated by subcloning the MAPK15 gene, excised from pCEFL-HA-MAPK15, upstream the IRES sequence, with BamHI and XbaI restriction sites.
Cell culture and transfections
293T and HeLa cells were maintained in DMEM (PAA, E15–009) supplemented with 10% fetal bovine serum (PAA, A15–151), 2 mM L-glutamine and 100 units/ml penicillin-streptomycin at 37°C in an atmosphere of 5% CO2/air. HeLa cells stably expressing GFP-LC3B were created transfecting HeLa cells with the previously described pCEFL GFP-LC3B plasmid, and selecting cells with 1 mg/ml G418 (Genespin, STS-G418). HeLa T-RexBCR-ABL1 cells were created by transfecting HeLa T-Rex cells with the pcDNA4-Tet-On-BCR-ABL plasmid and selecting them with 200 ug/ml zeocin until cells were stabilized. HeLa T-RexBCR-ABL1 cells were maintained in DMEM supplemented with 10% fetal bovine serum (Clonetech, 631106), 2 mM L-glutamine, 5 ug/ml blasticidin and 100 units/ml penicillin-streptomycin at 37°C in an atmosphere of 5% CO2/air. In HeLa T-RexBCR-ABL1, the expression of the BCR-ABL1 protein is inducible by addition of doxycycline. HeLa cells stably expressing pCEFL and scrambled (SCR) shRNA, pCEFL and MAPK15 shRNA, BCR-ABL1 and SCR shRNA, or BCR-ABL1 and MAPK15 shRNA respectively were transfected with pCEFL empty vector, pCEFL-BCR-ABL, pGIPZ shSCR or pGIPZ shMAPK15 and selected for respective antibiotic resistances for G418 (1 mg/ml) and puromycin (2 ug/ml). The stably expressing cells were then plated at a limiting dilution in 96-well plates to obtain single cell clones.293T and HeLa cells were maintained in RPMI 1640 (PAA, E15–039) supplemented with 10% fetal bovine serum (PAA, A15–151), 2 mM L-glutamine and 100 units/ml penicillin-streptomycin at 37°C in an atmosphere of 5% CO2/air. K562 cells stably expressing shSCR and shMAPK15 were generated by electroporating cells with respective shRNAs and by selecting with Puromycin (2 ug/ml) whereas K562 expressing WT as well as the AXXA and KD MAPK15 mutants were generated by electroporating cells with the above-described corresponding plasmids and selected with G418 (1 mg/ml).For immunofluorescence experiments and western blot analysis, 5 × 104 cells were seeded in 12-well plates (2 × 105 cells in 6-well plates) and transfected with 200 ng (500 ng in 6-well plates) of each expression vector, using Lipofectamine LTX (Life Technologies, 15338500). All experiments were performed, unless specified, 24 h after transfection. For confocal microscopy experiments, 2.5 × 104 cells were seeded on coverslips placed in 12-well plates. Each sample was transfected with 200 ng of each plasmid using Lipofectamine LTX.
RNA interference
MAPK15-specific siRNA (target sequence for MAPK15 #01 siRNA 5′-GCTTGGAGGCTACTCCC-3′, for MAPK15 #02 siRNA 5′-GACAGATGCCCAGAGAACA-3′, for MAPK15 #03 siRNA 5′-CCTGGTGTTTGAGTTTATG-3′) and nonsilencing siRNA (scrambled, SCR; target sequence 5′-AATTCTCCGAACGTGTCACGT-3′) were obtained from Qiagen. HeLa cells were transfected with siRNA at a final concentration of 5 nM using HiPerFect (Qiagen, 301707), according to the manufacturer’s instructions. Samples were analyzed, unless specified, 72 h after transfection.
Western blots
Total lysates were obtained by resuspending washed cellular pellet fractions in MAPK lysis buffer (20 mM HEPES, pH 7.5, 10 mM EGTA, 40 mM β-glycerophosphate, 1% NP-40 (Sigma Aldrich, I3021), 2.5 mM MgCl2, 2 mM orthovanadate, 2 mM NaF, 1 mM DTT, Roche protease inhibitors cocktail (Roche Diagnostics, 05056489001). Proteins were quantified by the Bradford assay and, before loading, Laemmli 5X was added to the proteins which were incubated for 5 min at 95°C. Then, proteins were loaded on SDS-PAGE poly-acrylamide gel, transferred to Immobilon-P PVDF membrane (Millipore, IPVH00010), probed with the appropriate antibodies, and detected by enhanced chemoluminescence (ECL Prime; GE Healthcare, RPN2232). Images were then acquired with a LAS 4000 imager (GE Healthcare, Milan, Italy). Densitometric analysis of western blots was performed with NIH ImageJ 1.43u (National Institutes of Health).
Coimmunoprecipitations
Whole cell lysates were obtained by resuspending washed pellet fractions in the above-mentioned MAPK lysis buffer. Lysates were incubated with appropriate antibodies for 2 h at 4°C. Then, immunocomplexes were purified by incubating the lysates for 45 min with protein G Mag Sepharose Xtra (GE Healthcare, 28–9670–70). After 5 washes, the immunocomplexes were resuspended in 2X Laemmli buffer and subjected to western blot analysis. For endogenous coimmunoprecipitation experiments, 5 mg of K562 cell lysates were used.
Affinity purifications
Whole cell lysates were obtained by resuspending washed pellet fractions in the above-mentioned MAPK lysis buffer. Lysates were incubated with Glutathione Magnetic Beads (Pierce, 88822) for 2 h at 4°C. After 5 washes, protein-beads complexes were resuspended in 2X Laemmli buffer and subjected to western blot analysis.
Immunofluorescence (IF)
Cells were washed with phosphate-buffered saline (PBS; Oxoid, BR0014G), then fixed with 4% paraformaldehyde in PBS for 20 min and permeabilized with 0.2% Triton X-100 (Sigma Aldrich, T8787) solution or 100 μg/ml digitonin solution (Life Technologies, BN2006) for 20 min, as indicated. Cells were incubated with the appropriate primary antibodies for 1 h, washed 3 times with PBS, and then incubated for 30 min with appropriate Alexa Fluor 488-conjugated (Life Technologies, A21202), Alexa Fluor 555-conjugated (Life Technologies, A31272) or Alexa Fluor 647-conjugated (Life Technologies, A21245) secondary antibodies and then washed again 3 times in PBS. Nuclei were stained with a solution of 1.5 μM of 4′,6-diamidino-2-phenylindole (DAPI; Sigma Aldrich, D9542) in PBS for 5 min. Coverslips were mounted in Fluorescence Mounting Medium (Dako, S3023). Samples were visualized on a TSC SP5 confocal microscope (Leica Microsystems, Germany, Mannheim) installed on an inverted LEICA DMI 6000CS microscope (Leica Microsystems, Germany, Mannheim) and equipped with an oil immersion PlanApo 63X 1.4 NA objective. Images were acquired using the LAS AF acquisition software (Leica Microsystems).
Anchorage-independent growth
HeLa cells were transient transfected with the indicated DNA plasmid or siRNA. After recovery, cells were seeded at 300 cells per 9-cm dish in DMEM, supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin-streptomycin and 0.35% agar, on a more dense layer of the same medium (0.5% agar). The cultures were maintained in a 37°C, 5% CO2 incubator for 14 d. Colonies were stained with 4 mg/ml iodonitrotetrazolium chloride (Sigma Aldrich, I8377) and scored using a microscope.
Cell count
Briefly, cells were seeded in 6-well plates at 2 × 105 cells per well in triplicate. Then cells were transfected and 72 h post transfection cell number was determined by counting the viable cells in a hemocytometer by trypan blue dye exclusion assay.
Cell cycle analysis
Cells were harvested and counted. Then, 1 × 106 cells were pelleted and resuspended in 1 ml Nicoletti solution (propidium iodide 50 mg/liter in 0.1% sodium citrate plus 0.1% Triton X-100). Cells were incubated in the dark at 4°C for 60 min and analyzed in a flow cytometer (FACSCanto II, BD Biosciences, Italy, Milan).
Xenografts
All protocols involving animals have been approved by the internal Animal Welfare Body and by Italian Ministero della Salute. For each injection, 5 × 106 K562 cells were resuspended in 100 μl PBS. Six-week-old athymic nude female mice (Harlan Laboratories) were injected in both flanks using a 21-gauge needle. The mice were anesthetized with isoflurane throughout the procedure. Five mice were injected on both flanks, for a total of 10 xenograft tumors per group. The animals were then monitored for tumor growth and tumor size was measured twice a week with a caliper (2Biological Instruments). Tumor volumes were calculated using the formula V = W2 × L × 0.5, where W and L are tumor width and length, respectively.
Dot count, Pearson correlation, and statistical analysis
For the LC3B-positive dot count, we performed intensitometric analysis of fluorescence using the Quantitation Module of Volocity software (PerkinElmer Life Science). Pearson correlation was also measured by the Quantitation Module of Volocity software. Dot count and colocalization rate were subjected to statistical analysis. Measures were obtained by analyzing at least 400 cells/sample from 3 different experiments. Significance (P value) was assessed by one-way ANOVA test. Asterisks were attributed for the following significance values: P < 0 .05 (*), P < 0 .01 (**), P < 0 .001 (***).
Authors: Andrew S Dixon; Jonathan E Constance; Tomoyuki Tanaka; Terence H Rabbitts; Carol S Lim Journal: Pharm Res Date: 2011-12-20 Impact factor: 4.200
Authors: Dennis J Goussetis; Elias Gounaris; Edward J Wu; Eliza Vakana; Bhumika Sharma; Matthew Bogyo; Jessica K Altman; Leonidas C Platanias Journal: Blood Date: 2012-08-16 Impact factor: 22.113
Authors: Y Kamitsuji; J Kuroda; S Kimura; S Toyokuni; K Watanabe; E Ashihara; H Tanaka; Y Yui; M Watanabe; H Matsubara; Y Mizushima; Y Hiraumi; E Kawata; T Yoshikawa; T Maekawa; T Nakahata; S Adachi Journal: Cell Death Differ Date: 2008-07-11 Impact factor: 15.828
Authors: Daniel J Klionsky; Fabio C Abdalla; Hagai Abeliovich; Robert T Abraham; Abraham Acevedo-Arozena; Khosrow Adeli; Lotta Agholme; Maria Agnello; Patrizia Agostinis; Julio A Aguirre-Ghiso; Hyung Jun Ahn; Ouardia Ait-Mohamed; Slimane Ait-Si-Ali; Takahiko Akematsu; Shizuo Akira; Hesham M Al-Younes; Munir A Al-Zeer; Matthew L Albert; Roger L Albin; Javier Alegre-Abarrategui; Maria Francesca Aleo; Mehrdad Alirezaei; Alexandru Almasan; Maylin Almonte-Becerril; Atsuo Amano; Ravi Amaravadi; Shoba Amarnath; Amal O Amer; Nathalie Andrieu-Abadie; Vellareddy Anantharam; David K Ann; Shailendra Anoopkumar-Dukie; Hiroshi Aoki; Nadezda Apostolova; Giuseppe Arancia; John P Aris; Katsuhiko Asanuma; Nana Y O Asare; Hisashi Ashida; Valerie Askanas; David S Askew; Patrick Auberger; Misuzu Baba; Steven K Backues; Eric H Baehrecke; Ben A Bahr; Xue-Yuan Bai; Yannick Bailly; Robert Baiocchi; Giulia Baldini; Walter Balduini; Andrea Ballabio; Bruce A Bamber; Edward T W Bampton; Gábor Bánhegyi; Clinton R Bartholomew; Diane C Bassham; Robert C Bast; Henri Batoko; Boon-Huat Bay; Isabelle Beau; Daniel M Béchet; Thomas J Begley; Christian Behl; Christian Behrends; Soumeya Bekri; Bryan Bellaire; Linda J Bendall; Luca Benetti; Laura Berliocchi; Henri Bernardi; Francesca Bernassola; Sébastien Besteiro; Ingrid Bhatia-Kissova; Xiaoning Bi; Martine Biard-Piechaczyk; Janice S Blum; Lawrence H Boise; Paolo Bonaldo; David L Boone; Beat C Bornhauser; Karina R Bortoluci; Ioannis Bossis; Frédéric Bost; Jean-Pierre Bourquin; Patricia Boya; Michaël Boyer-Guittaut; Peter V Bozhkov; Nathan R Brady; Claudio Brancolini; Andreas Brech; Jay E Brenman; Ana Brennand; Emery H Bresnick; Patrick Brest; Dave Bridges; Molly L Bristol; Paul S Brookes; Eric J Brown; John H Brumell; Nicola Brunetti-Pierri; Ulf T Brunk; Dennis E Bulman; Scott J Bultman; Geert Bultynck; Lena F Burbulla; Wilfried Bursch; Jonathan P Butchar; Wanda Buzgariu; Sergio P Bydlowski; Ken Cadwell; Monika Cahová; Dongsheng Cai; Jiyang Cai; Qian Cai; Bruno Calabretta; Javier Calvo-Garrido; Nadine Camougrand; Michelangelo Campanella; Jenny Campos-Salinas; Eleonora Candi; Lizhi Cao; Allan B Caplan; Simon R Carding; Sandra M Cardoso; Jennifer S Carew; Cathleen R Carlin; Virginie Carmignac; Leticia A M Carneiro; Serena Carra; Rosario A Caruso; Giorgio Casari; Caty Casas; Roberta Castino; Eduardo Cebollero; Francesco Cecconi; Jean Celli; Hassan Chaachouay; Han-Jung Chae; Chee-Yin Chai; David C Chan; Edmond Y Chan; Raymond Chuen-Chung Chang; Chi-Ming Che; Ching-Chow Chen; Guang-Chao Chen; Guo-Qiang Chen; Min Chen; Quan Chen; Steve S-L Chen; WenLi Chen; Xi Chen; Xiangmei Chen; Xiequn Chen; Ye-Guang Chen; Yingyu Chen; Yongqiang Chen; Yu-Jen Chen; Zhixiang Chen; Alan Cheng; Christopher H K Cheng; Yan Cheng; Heesun Cheong; Jae-Ho Cheong; Sara Cherry; Russ Chess-Williams; Zelda H Cheung; Eric Chevet; Hui-Ling Chiang; Roberto Chiarelli; Tomoki Chiba; Lih-Shen Chin; Shih-Hwa Chiou; Francis V Chisari; Chi Hin Cho; Dong-Hyung Cho; Augustine M K Choi; DooSeok Choi; Kyeong Sook Choi; Mary E Choi; Salem Chouaib; Divaker Choubey; Vinay Choubey; Charleen T Chu; Tsung-Hsien Chuang; Sheau-Huei Chueh; Taehoon Chun; Yong-Joon Chwae; Mee-Len Chye; Roberto Ciarcia; Maria R Ciriolo; Michael J Clague; Robert S B Clark; Peter G H Clarke; Robert Clarke; Patrice Codogno; Hilary A Coller; María I Colombo; Sergio Comincini; Maria Condello; Fabrizio Condorelli; Mark R Cookson; Graham H Coombs; Isabelle Coppens; Ramon Corbalan; Pascale Cossart; Paola Costelli; Safia Costes; Ana Coto-Montes; Eduardo Couve; Fraser P Coxon; James M Cregg; José L Crespo; Marianne J Cronjé; Ana Maria Cuervo; Joseph J Cullen; Mark J Czaja; Marcello D'Amelio; Arlette Darfeuille-Michaud; Lester M Davids; Faith E Davies; Massimo De Felici; John F de Groot; Cornelis A M de Haan; Luisa De Martino; Angelo De Milito; Vincenzo De Tata; Jayanta Debnath; Alexei Degterev; Benjamin Dehay; Lea M D Delbridge; Francesca Demarchi; Yi Zhen Deng; Jörn Dengjel; Paul Dent; Donna Denton; Vojo Deretic; Shyamal D Desai; Rodney J Devenish; Mario Di Gioacchino; Gilbert Di Paolo; Chiara Di Pietro; Guillermo Díaz-Araya; Inés Díaz-Laviada; Maria T Diaz-Meco; Javier Diaz-Nido; Ivan Dikic; Savithramma P Dinesh-Kumar; Wen-Xing Ding; Clark W Distelhorst; Abhinav Diwan; Mojgan Djavaheri-Mergny; Svetlana Dokudovskaya; Zheng Dong; Frank C Dorsey; Victor Dosenko; James J Dowling; Stephen Doxsey; Marlène Dreux; Mark E Drew; Qiuhong Duan; Michel A Duchosal; Karen Duff; Isabelle Dugail; Madeleine Durbeej; Michael Duszenko; Charles L Edelstein; Aimee L Edinger; Gustavo Egea; Ludwig Eichinger; N Tony Eissa; Suhendan Ekmekcioglu; Wafik S El-Deiry; Zvulun Elazar; Mohamed Elgendy; Lisa M Ellerby; Kai Er Eng; Anna-Mart Engelbrecht; Simone Engelender; Jekaterina Erenpreisa; Ricardo Escalante; Audrey Esclatine; Eeva-Liisa Eskelinen; Lucile Espert; Virginia Espina; Huizhou Fan; Jia Fan; Qi-Wen Fan; Zhen Fan; Shengyun Fang; Yongqi Fang; Manolis Fanto; Alessandro Fanzani; Thomas Farkas; Jean-Claude Farré; Mathias Faure; Marcus Fechheimer; Carl G Feng; Jian Feng; Qili Feng; Youji Feng; László Fésüs; Ralph Feuer; Maria E Figueiredo-Pereira; Gian Maria Fimia; Diane C Fingar; Steven Finkbeiner; Toren Finkel; Kim D Finley; Filomena Fiorito; Edward A Fisher; Paul B Fisher; Marc Flajolet; Maria L Florez-McClure; Salvatore Florio; Edward A Fon; Francesco Fornai; Franco Fortunato; Rati Fotedar; Daniel H Fowler; Howard S Fox; Rodrigo Franco; Lisa B Frankel; Marc Fransen; José M Fuentes; Juan Fueyo; Jun Fujii; Kozo Fujisaki; Eriko Fujita; Mitsunori Fukuda; Ruth H Furukawa; Matthias Gaestel; Philippe Gailly; Malgorzata Gajewska; Brigitte Galliot; Vincent Galy; Subramaniam Ganesh; Barry Ganetzky; Ian G Ganley; Fen-Biao Gao; George F Gao; Jinming Gao; Lorena Garcia; Guillermo Garcia-Manero; Mikel Garcia-Marcos; Marjan Garmyn; Andrei L Gartel; Evelina Gatti; Mathias Gautel; Thomas R Gawriluk; Matthew E Gegg; Jiefei Geng; Marc Germain; Jason E Gestwicki; David A Gewirtz; Saeid Ghavami; Pradipta Ghosh; Anna M Giammarioli; Alexandra N Giatromanolaki; Spencer B Gibson; Robert W Gilkerson; Michael L Ginger; Henry N Ginsberg; Jakub Golab; Michael S Goligorsky; Pierre Golstein; Candelaria Gomez-Manzano; Ebru Goncu; Céline Gongora; Claudio D Gonzalez; Ramon Gonzalez; Cristina González-Estévez; Rosa Ana González-Polo; Elena Gonzalez-Rey; Nikolai V Gorbunov; Sharon Gorski; Sandro Goruppi; Roberta A Gottlieb; Devrim Gozuacik; Giovanna Elvira Granato; Gary D Grant; Kim N Green; Aleš Gregorc; Frédéric Gros; Charles Grose; Thomas W Grunt; Philippe Gual; Jun-Lin Guan; Kun-Liang Guan; Sylvie M Guichard; Anna S Gukovskaya; Ilya Gukovsky; Jan Gunst; Asa B Gustafsson; Andrew J Halayko; Amber N Hale; Sandra K Halonen; Maho Hamasaki; Feng Han; Ting Han; Michael K Hancock; Malene Hansen; Hisashi Harada; Masaru Harada; Stefan E Hardt; J Wade Harper; Adrian L Harris; James Harris; Steven D Harris; Makoto Hashimoto; Jeffrey A Haspel; Shin-ichiro Hayashi; Lori A Hazelhurst; Congcong He; You-Wen He; Marie-Joseé Hébert; Kim A Heidenreich; Miep H Helfrich; Gudmundur V Helgason; Elizabeth P Henske; Brian Herman; Paul K Herman; Claudio Hetz; Sabine Hilfiker; Joseph A Hill; Lynne J Hocking; Paul Hofman; Thomas G Hofmann; Jörg Höhfeld; Tessa L Holyoake; Ming-Huang Hong; David A Hood; Gökhan S Hotamisligil; Ewout J Houwerzijl; Maria Høyer-Hansen; Bingren Hu; Chien-An A Hu; Hong-Ming Hu; Ya Hua; Canhua Huang; Ju Huang; Shengbing Huang; Wei-Pang Huang; Tobias B Huber; Won-Ki Huh; Tai-Ho Hung; Ted R Hupp; Gang Min Hur; James B Hurley; Sabah N A Hussain; Patrick J Hussey; Jung Jin Hwang; Seungmin Hwang; Atsuhiro Ichihara; Shirin Ilkhanizadeh; Ken Inoki; Takeshi Into; Valentina Iovane; Juan L Iovanna; Nancy Y Ip; Yoshitaka Isaka; Hiroyuki Ishida; Ciro Isidoro; Ken-ichi Isobe; Akiko Iwasaki; Marta Izquierdo; Yotaro Izumi; Panu M Jaakkola; Marja Jäättelä; George R Jackson; William T Jackson; Bassam Janji; Marina Jendrach; Ju-Hong Jeon; Eui-Bae Jeung; Hong Jiang; Hongchi Jiang; Jean X Jiang; Ming Jiang; Qing Jiang; Xuejun Jiang; Xuejun Jiang; Alberto Jiménez; Meiyan Jin; Shengkan Jin; Cheol O Joe; Terje Johansen; Daniel E Johnson; Gail V W Johnson; Nicola L Jones; Bertrand Joseph; Suresh K Joseph; Annie M Joubert; Gábor Juhász; Lucienne Juillerat-Jeanneret; Chang Hwa Jung; Yong-Keun Jung; Kai Kaarniranta; Allen Kaasik; Tomohiro Kabuta; Motoni Kadowaki; Katarina Kagedal; Yoshiaki Kamada; Vitaliy O Kaminskyy; Harm H Kampinga; Hiromitsu Kanamori; Chanhee Kang; Khong Bee Kang; Kwang Il Kang; Rui Kang; Yoon-A Kang; Tomotake Kanki; Thirumala-Devi Kanneganti; Haruo Kanno; Anumantha G Kanthasamy; Arthi Kanthasamy; Vassiliki Karantza; Gur P Kaushal; Susmita Kaushik; Yoshinori Kawazoe; Po-Yuan Ke; John H Kehrl; Ameeta Kelekar; Claus Kerkhoff; David H Kessel; Hany Khalil; Jan A K W Kiel; Amy A Kiger; Akio Kihara; Deok Ryong Kim; Do-Hyung Kim; Dong-Hou Kim; Eun-Kyoung Kim; Hyung-Ryong Kim; Jae-Sung Kim; Jeong Hun Kim; Jin Cheon Kim; John K Kim; Peter K Kim; Seong Who Kim; Yong-Sun Kim; Yonghyun Kim; Adi Kimchi; Alec C Kimmelman; Jason S King; Timothy J Kinsella; Vladimir Kirkin; Lorrie A Kirshenbaum; Katsuhiko Kitamoto; Kaio Kitazato; Ludger Klein; Walter T Klimecki; Jochen Klucken; Erwin Knecht; Ben C B Ko; Jan C Koch; Hiroshi Koga; Jae-Young Koh; Young Ho Koh; Masato Koike; Masaaki Komatsu; Eiki Kominami; Hee Jeong Kong; Wei-Jia Kong; Viktor I Korolchuk; Yaichiro Kotake; Michael I Koukourakis; Juan B Kouri Flores; Attila L Kovács; Claudine Kraft; Dimitri Krainc; Helmut Krämer; Carole Kretz-Remy; Anna M Krichevsky; Guido Kroemer; Rejko Krüger; Oleg Krut; Nicholas T Ktistakis; Chia-Yi Kuan; Roza Kucharczyk; Ashok Kumar; Raj Kumar; Sharad Kumar; Mondira Kundu; Hsing-Jien Kung; Tino Kurz; Ho Jeong Kwon; Albert R La Spada; Frank Lafont; Trond Lamark; Jacques Landry; Jon D Lane; Pierre Lapaquette; Jocelyn F Laporte; Lajos László; Sergio Lavandero; Josée N Lavoie; Robert Layfield; Pedro A Lazo; Weidong Le; Laurent Le Cam; Daniel J Ledbetter; Alvin J X Lee; Byung-Wan Lee; Gyun Min Lee; Jongdae Lee; Ju-Hyun Lee; Michael Lee; Myung-Shik Lee; Sug Hyung Lee; Christiaan Leeuwenburgh; Patrick Legembre; Renaud Legouis; Michael Lehmann; Huan-Yao Lei; Qun-Ying Lei; David A Leib; José Leiro; John J Lemasters; Antoinette Lemoine; Maciej S Lesniak; Dina Lev; Victor V Levenson; Beth Levine; Efrat Levy; Faqiang Li; Jun-Lin Li; Lian Li; Sheng Li; Weijie Li; Xue-Jun Li; Yan-bo Li; Yi-Ping Li; Chengyu Liang; Qiangrong Liang; Yung-Feng Liao; Pawel P Liberski; Andrew Lieberman; Hyunjung J Lim; Kah-Leong Lim; Kyu Lim; Chiou-Feng Lin; Fu-Cheng Lin; Jian Lin; Jiandie D Lin; Kui Lin; Wan-Wan Lin; Weei-Chin Lin; Yi-Ling Lin; Rafael Linden; Paul Lingor; Jennifer Lippincott-Schwartz; Michael P Lisanti; Paloma B Liton; Bo Liu; Chun-Feng Liu; Kaiyu Liu; Leyuan Liu; Qiong A Liu; Wei Liu; Young-Chau Liu; Yule Liu; Richard A Lockshin; Chun-Nam Lok; Sagar Lonial; Benjamin Loos; Gabriel Lopez-Berestein; Carlos López-Otín; Laura Lossi; Michael T Lotze; Peter Lőw; Binfeng Lu; Bingwei Lu; Bo Lu; Zhen Lu; Frédéric Luciano; Nicholas W Lukacs; Anders H Lund; Melinda A Lynch-Day; Yong Ma; Fernando Macian; Jeff P MacKeigan; Kay F Macleod; Frank Madeo; Luigi Maiuri; Maria Chiara Maiuri; Davide Malagoli; May Christine V Malicdan; Walter Malorni; Na Man; Eva-Maria Mandelkow; Stéphen Manon; Irena Manov; Kai Mao; Xiang Mao; Zixu Mao; Philippe Marambaud; Daniela Marazziti; Yves L Marcel; Katie Marchbank; Piero Marchetti; Stefan J Marciniak; Mateus Marcondes; Mohsen Mardi; Gabriella Marfe; Guillermo Mariño; Maria Markaki; Mark R Marten; Seamus J Martin; Camille Martinand-Mari; Wim Martinet; Marta Martinez-Vicente; Matilde Masini; Paola Matarrese; Saburo Matsuo; Raffaele Matteoni; Andreas Mayer; Nathalie M Mazure; David J McConkey; Melanie J McConnell; Catherine McDermott; Christine McDonald; Gerald M McInerney; Sharon L McKenna; BethAnn McLaughlin; Pamela J McLean; Christopher R McMaster; G Angus McQuibban; Alfred J Meijer; Miriam H Meisler; Alicia Meléndez; Thomas J Melia; Gerry Melino; Maria A Mena; Javier A Menendez; Rubem F S Menna-Barreto; Manoj B Menon; Fiona M Menzies; Carol A Mercer; Adalberto Merighi; Diane E Merry; Stefania Meschini; Christian G Meyer; Thomas F Meyer; Chao-Yu Miao; Jun-Ying Miao; Paul A M Michels; Carine Michiels; Dalibor Mijaljica; Ana Milojkovic; Saverio Minucci; Clelia Miracco; Cindy K Miranti; Ioannis Mitroulis; Keisuke Miyazawa; Noboru Mizushima; Baharia Mograbi; Simin Mohseni; Xavier Molero; Bertrand Mollereau; Faustino Mollinedo; Takashi Momoi; Iryna Monastyrska; Martha M Monick; Mervyn J Monteiro; Michael N Moore; Rodrigo Mora; Kevin Moreau; Paula I Moreira; Yuji Moriyasu; Jorge Moscat; Serge Mostowy; Jeremy C Mottram; Tomasz Motyl; Charbel E-H Moussa; Sylke Müller; Sylviane Muller; Karl Münger; Christian Münz; Leon O Murphy; Maureen E Murphy; Antonio Musarò; Indira Mysorekar; Eiichiro Nagata; Kazuhiro Nagata; Aimable Nahimana; Usha Nair; Toshiyuki Nakagawa; Kiichi Nakahira; Hiroyasu Nakano; Hitoshi Nakatogawa; Meera Nanjundan; Naweed I Naqvi; Derek P Narendra; Masashi Narita; Miguel Navarro; Steffan T Nawrocki; Taras Y Nazarko; Andriy Nemchenko; Mihai G Netea; Thomas P Neufeld; Paul A Ney; Ioannis P Nezis; Huu Phuc Nguyen; Daotai Nie; Ichizo Nishino; Corey Nislow; Ralph A Nixon; Takeshi Noda; Angelika A Noegel; Anna Nogalska; Satoru Noguchi; Lucia Notterpek; Ivana Novak; Tomoyoshi Nozaki; Nobuyuki Nukina; Thorsten Nürnberger; Beat Nyfeler; Keisuke Obara; Terry D Oberley; Salvatore Oddo; Michinaga Ogawa; Toya Ohashi; Koji Okamoto; Nancy L Oleinick; F Javier Oliver; Laura J Olsen; Stefan Olsson; Onya Opota; Timothy F Osborne; Gary K Ostrander; Kinya Otsu; Jing-hsiung James Ou; Mireille Ouimet; Michael Overholtzer; Bulent Ozpolat; Paolo Paganetti; Ugo Pagnini; Nicolas Pallet; Glen E Palmer; Camilla Palumbo; Tianhong Pan; Theocharis Panaretakis; Udai Bhan Pandey; Zuzana Papackova; Issidora Papassideri; Irmgard Paris; Junsoo Park; Ohkmae K Park; Jan B Parys; Katherine R Parzych; Susann Patschan; Cam Patterson; Sophie Pattingre; John M Pawelek; Jianxin Peng; David H Perlmutter; Ida Perrotta; George Perry; Shazib Pervaiz; Matthias Peter; Godefridus J Peters; Morten Petersen; Goran Petrovski; James M Phang; Mauro Piacentini; Philippe Pierre; Valérie Pierrefite-Carle; Gérard Pierron; Ronit Pinkas-Kramarski; Antonio Piras; Natik Piri; Leonidas C Platanias; Stefanie Pöggeler; Marc Poirot; Angelo Poletti; Christian Poüs; Mercedes Pozuelo-Rubio; Mette Prætorius-Ibba; Anil Prasad; Mark Prescott; Muriel Priault; Nathalie Produit-Zengaffinen; Ann Progulske-Fox; Tassula Proikas-Cezanne; Serge Przedborski; Karin Przyklenk; Rosa Puertollano; Julien Puyal; Shu-Bing Qian; Liang Qin; Zheng-Hong Qin; Susan E Quaggin; Nina Raben; Hannah Rabinowich; Simon W Rabkin; Irfan Rahman; Abdelhaq Rami; Georg Ramm; Glenn Randall; Felix Randow; V Ashutosh Rao; Jeffrey C Rathmell; Brinda Ravikumar; Swapan K Ray; Bruce H Reed; John C Reed; Fulvio Reggiori; Anne Régnier-Vigouroux; Andreas S Reichert; John J Reiners; Russel J Reiter; Jun Ren; José L Revuelta; Christopher J Rhodes; Konstantinos Ritis; Elizete Rizzo; Jeffrey Robbins; Michel Roberge; Hernan Roca; Maria C Roccheri; Stephane Rocchi; H Peter Rodemann; Santiago Rodríguez de Córdoba; Bärbel Rohrer; Igor B Roninson; Kirill Rosen; Magdalena M Rost-Roszkowska; Mustapha Rouis; Kasper M A Rouschop; Francesca Rovetta; Brian P Rubin; David C Rubinsztein; Klaus Ruckdeschel; Edmund B Rucker; Assaf Rudich; Emil Rudolf; Nelson Ruiz-Opazo; Rossella Russo; Tor Erik Rusten; Kevin M Ryan; Stefan W Ryter; David M Sabatini; Junichi Sadoshima; Tapas Saha; Tatsuya Saitoh; Hiroshi Sakagami; Yasuyoshi Sakai; Ghasem Hoseini Salekdeh; Paolo Salomoni; Paul M Salvaterra; Guy Salvesen; Rosa Salvioli; Anthony M J Sanchez; José A Sánchez-Alcázar; Ricardo Sánchez-Prieto; Marco Sandri; Uma Sankar; Poonam Sansanwal; Laura Santambrogio; Shweta Saran; Sovan Sarkar; Minnie Sarwal; Chihiro Sasakawa; Ausra Sasnauskiene; Miklós Sass; Ken Sato; Miyuki Sato; Anthony H V Schapira; Michael Scharl; Hermann M Schätzl; Wiep Scheper; Stefano Schiaffino; Claudio Schneider; Marion E Schneider; Regine Schneider-Stock; Patricia V Schoenlein; Daniel F Schorderet; Christoph Schüller; Gary K Schwartz; Luca Scorrano; Linda Sealy; Per O Seglen; Juan Segura-Aguilar; Iban Seiliez; Oleksandr Seleverstov; Christian Sell; Jong Bok Seo; Duska Separovic; Vijayasaradhi Setaluri; Takao Setoguchi; Carmine Settembre; John J Shacka; Mala Shanmugam; Irving M Shapiro; Eitan Shaulian; Reuben J Shaw; James H Shelhamer; Han-Ming Shen; Wei-Chiang Shen; Zu-Hang Sheng; Yang Shi; Kenichi Shibuya; Yoshihiro Shidoji; Jeng-Jer Shieh; Chwen-Ming Shih; Yohta Shimada; Shigeomi Shimizu; Takahiro Shintani; Orian S Shirihai; Gordon C Shore; Andriy A Sibirny; Stan B Sidhu; Beata Sikorska; Elaine C M Silva-Zacarin; Alison Simmons; Anna Katharina Simon; Hans-Uwe Simon; Cristiano Simone; Anne Simonsen; David A Sinclair; Rajat Singh; Debasish Sinha; Frank A Sinicrope; Agnieszka Sirko; Parco M Siu; Efthimios Sivridis; Vojtech Skop; Vladimir P Skulachev; Ruth S Slack; Soraya S Smaili; Duncan R Smith; Maria S Soengas; Thierry Soldati; Xueqin Song; Anil K Sood; Tuck Wah Soong; Federica Sotgia; Stephen A Spector; Claudia D Spies; Wolfdieter Springer; Srinivasa M Srinivasula; Leonidas Stefanis; Joan S Steffan; Ruediger Stendel; Harald Stenmark; Anastasis Stephanou; Stephan T Stern; Cinthya Sternberg; Björn Stork; Peter Strålfors; Carlos S Subauste; Xinbing Sui; David Sulzer; Jiaren Sun; Shi-Yong Sun; Zhi-Jun Sun; Joseph J Y Sung; Kuninori Suzuki; Toshihiko Suzuki; Michele S Swanson; Charles Swanton; Sean T Sweeney; Lai-King Sy; Gyorgy Szabadkai; Ira Tabas; Heinrich Taegtmeyer; Marco Tafani; Krisztina Takács-Vellai; Yoshitaka Takano; Kaoru Takegawa; Genzou Takemura; Fumihiko Takeshita; Nicholas J Talbot; Kevin S W Tan; Keiji Tanaka; Kozo Tanaka; Daolin Tang; Dingzhong Tang; Isei Tanida; Bakhos A Tannous; Nektarios Tavernarakis; Graham S Taylor; Gregory A Taylor; J Paul Taylor; Lance S Terada; Alexei Terman; Gianluca Tettamanti; Karin Thevissen; Craig B Thompson; Andrew Thorburn; Michael Thumm; FengFeng Tian; Yuan Tian; Glauco Tocchini-Valentini; Aviva M Tolkovsky; Yasuhiko Tomino; Lars Tönges; Sharon A Tooze; Cathy Tournier; John Tower; Roberto Towns; Vladimir Trajkovic; Leonardo H Travassos; Ting-Fen Tsai; Mario P Tschan; Takeshi Tsubata; Allan Tsung; Boris Turk; Lorianne S Turner; Suresh C Tyagi; Yasuo Uchiyama; Takashi Ueno; Midori Umekawa; Rika Umemiya-Shirafuji; Vivek K Unni; Maria I Vaccaro; Enza Maria Valente; Greet Van den Berghe; Ida J van der Klei; Wouter van Doorn; Linda F van Dyk; Marjolein van Egmond; Leo A van Grunsven; Peter Vandenabeele; Wim P Vandenberghe; Ilse Vanhorebeek; Eva C Vaquero; Guillermo Velasco; Tibor Vellai; Jose Miguel Vicencio; Richard D Vierstra; Miquel Vila; Cécile Vindis; Giampietro Viola; Maria Teresa Viscomi; Olga V Voitsekhovskaja; Clarissa von Haefen; Marcela Votruba; Keiji Wada; Richard Wade-Martins; Cheryl L Walker; Craig M Walsh; Jochen Walter; Xiang-Bo Wan; Aimin Wang; Chenguang Wang; Dawei Wang; Fan Wang; Fen Wang; Guanghui Wang; Haichao Wang; Hong-Gang Wang; Horng-Dar Wang; Jin Wang; Ke Wang; Mei Wang; Richard C Wang; Xinglong Wang; Xuejun Wang; Ying-Jan Wang; Yipeng Wang; Zhen Wang; Zhigang Charles Wang; Zhinong Wang; Derick G Wansink; Diane M Ward; Hirotaka Watada; Sarah L Waters; Paul Webster; Lixin Wei; Conrad C Weihl; William A Weiss; Scott M Welford; Long-Ping Wen; Caroline A Whitehouse; J Lindsay Whitton; Alexander J Whitworth; Tom Wileman; John W Wiley; Simon Wilkinson; Dieter Willbold; Roger L Williams; Peter R Williamson; Bradly G Wouters; Chenghan Wu; Dao-Cheng Wu; William K K Wu; Andreas Wyttenbach; Ramnik J Xavier; Zhijun Xi; Pu Xia; Gengfu Xiao; Zhiping Xie; Zhonglin Xie; Da-zhi Xu; Jianzhen Xu; Liang Xu; Xiaolei Xu; Ai Yamamoto; Akitsugu Yamamoto; Shunhei Yamashina; Michiaki Yamashita; Xianghua Yan; Mitsuhiro Yanagida; Dun-Sheng Yang; Elizabeth Yang; Jin-Ming Yang; Shi Yu Yang; Wannian Yang; Wei Yuan Yang; Zhifen Yang; Meng-Chao Yao; Tso-Pang Yao; Behzad Yeganeh; Wei-Lien Yen; Jia-jing Yin; Xiao-Ming Yin; Ook-Joon Yoo; Gyesoon Yoon; Seung-Yong Yoon; Tomohiro Yorimitsu; Yuko Yoshikawa; Tamotsu Yoshimori; Kohki Yoshimoto; Ho Jin You; Richard J Youle; Anas Younes; Li Yu; Long Yu; Seong-Woon Yu; Wai Haung Yu; Zhi-Min Yuan; Zhenyu Yue; Cheol-Heui Yun; Michisuke Yuzaki; Olga Zabirnyk; Elaine Silva-Zacarin; David Zacks; Eldad Zacksenhaus; Nadia Zaffaroni; Zahra Zakeri; Herbert J Zeh; Scott O Zeitlin; Hong Zhang; Hui-Ling Zhang; Jianhua Zhang; Jing-Pu Zhang; Lin Zhang; Long Zhang; Ming-Yong Zhang; Xu Dong Zhang; Mantong Zhao; Yi-Fang Zhao; Ying Zhao; Zhizhuang J Zhao; Xiaoxiang Zheng; Boris Zhivotovsky; Qing Zhong; Cong-Zhao Zhou; Changlian Zhu; Wei-Guo Zhu; Xiao-Feng Zhu; Xiongwei Zhu; Yuangang Zhu; Teresa Zoladek; Wei-Xing Zong; Antonio Zorzano; Jürgen Zschocke; Brian Zuckerbraun Journal: Autophagy Date: 2012-04 Impact factor: 16.016
Authors: C Drullion; C Trégoat; V Lagarde; S Tan; R Gioia; M Priault; M Djavaheri-Mergny; A Brisson; P Auberger; F-X Mahon; J-M Pasquet Journal: Cell Death Dis Date: 2012-08-16 Impact factor: 8.469
Authors: B J Altman; S R Jacobs; E F Mason; R D Michalek; A N MacIntyre; J L Coloff; O Ilkayeva; W Jia; Y-W He; J C Rathmell Journal: Oncogene Date: 2010-12-13 Impact factor: 9.867
Authors: Daniel J Klionsky; Amal Kamal Abdel-Aziz; Sara Abdelfatah; Mahmoud Abdellatif; Asghar Abdoli; Steffen Abel; Hagai Abeliovich; Marie H Abildgaard; Yakubu Princely Abudu; Abraham Acevedo-Arozena; Iannis E Adamopoulos; Khosrow Adeli; Timon E Adolph; Annagrazia Adornetto; Elma Aflaki; Galila Agam; Anupam Agarwal; Bharat B Aggarwal; Maria Agnello; Patrizia Agostinis; Javed N Agrewala; Alexander Agrotis; Patricia V Aguilar; S Tariq Ahmad; Zubair M Ahmed; Ulises Ahumada-Castro; Sonja Aits; Shu Aizawa; Yunus Akkoc; Tonia Akoumianaki; Hafize Aysin Akpinar; Ahmed M Al-Abd; Lina Al-Akra; Abeer Al-Gharaibeh; Moulay A Alaoui-Jamali; Simon Alberti; Elísabet Alcocer-Gómez; Cristiano Alessandri; Muhammad Ali; M Abdul Alim Al-Bari; Saeb Aliwaini; Javad Alizadeh; Eugènia Almacellas; Alexandru Almasan; Alicia Alonso; Guillermo D Alonso; Nihal Altan-Bonnet; Dario C Altieri; Élida M C Álvarez; Sara Alves; Cristine Alves da Costa; Mazen M Alzaharna; Marialaura Amadio; Consuelo Amantini; Cristina Amaral; Susanna Ambrosio; Amal O Amer; Veena Ammanathan; Zhenyi An; Stig U Andersen; Shaida A Andrabi; Magaiver Andrade-Silva; Allen M Andres; Sabrina Angelini; David Ann; Uche C Anozie; Mohammad Y Ansari; Pedro Antas; Adam Antebi; Zuriñe Antón; Tahira Anwar; Lionel Apetoh; Nadezda Apostolova; Toshiyuki Araki; Yasuhiro Araki; Kohei Arasaki; Wagner L Araújo; Jun Araya; Catherine Arden; Maria-Angeles Arévalo; Sandro Arguelles; Esperanza Arias; Jyothi Arikkath; Hirokazu Arimoto; Aileen R Ariosa; Darius Armstrong-James; Laetitia Arnauné-Pelloquin; Angeles Aroca; Daniela S Arroyo; Ivica Arsov; Rubén Artero; Dalia Maria Lucia Asaro; Michael Aschner; Milad Ashrafizadeh; Osnat Ashur-Fabian; Atanas G Atanasov; Alicia K Au; Patrick Auberger; Holger W Auner; Laure Aurelian; Riccardo Autelli; Laura Avagliano; Yenniffer Ávalos; Sanja Aveic; Célia Alexandra Aveleira; Tamar Avin-Wittenberg; Yucel Aydin; Scott Ayton; Srinivas Ayyadevara; Maria Azzopardi; Misuzu Baba; Jonathan M Backer; Steven K Backues; Dong-Hun Bae; Ok-Nam Bae; Soo Han Bae; Eric H Baehrecke; Ahruem Baek; Seung-Hoon Baek; Sung Hee Baek; Giacinto Bagetta; Agnieszka Bagniewska-Zadworna; Hua Bai; Jie Bai; Xiyuan Bai; Yidong Bai; Nandadulal Bairagi; Shounak Baksi; Teresa Balbi; Cosima T Baldari; Walter Balduini; Andrea Ballabio; Maria Ballester; Salma Balazadeh; Rena Balzan; Rina Bandopadhyay; Sreeparna Banerjee; Sulagna Banerjee; Ágnes Bánréti; Yan Bao; Mauricio S Baptista; Alessandra Baracca; Cristiana Barbati; Ariadna Bargiela; Daniela Barilà; Peter G Barlow; Sami J Barmada; Esther Barreiro; George E Barreto; Jiri Bartek; Bonnie Bartel; Alberto Bartolome; Gaurav R Barve; Suresh H Basagoudanavar; Diane C Bassham; Robert C Bast; Alakananda Basu; Henri Batoko; Isabella Batten; Etienne E Baulieu; Bradley L Baumgarner; Jagadeesh Bayry; Rupert Beale; Isabelle Beau; Florian Beaumatin; Luiz R G Bechara; George R Beck; Michael F Beers; Jakob Begun; Christian Behrends; Georg M N Behrens; Roberto Bei; Eloy Bejarano; Shai Bel; Christian Behl; Amine Belaid; Naïma Belgareh-Touzé; Cristina Bellarosa; Francesca Belleudi; Melissa Belló Pérez; Raquel Bello-Morales; Jackeline Soares de Oliveira Beltran; Sebastián Beltran; Doris Mangiaracina Benbrook; Mykolas Bendorius; Bruno A Benitez; Irene Benito-Cuesta; Julien Bensalem; Martin W Berchtold; Sabina Berezowska; Daniele Bergamaschi; Matteo Bergami; Andreas Bergmann; Laura Berliocchi; Clarisse Berlioz-Torrent; Amélie Bernard; Lionel Berthoux; Cagri G Besirli; Sebastien Besteiro; Virginie M Betin; Rudi Beyaert; Jelena S Bezbradica; Kiran Bhaskar; Ingrid Bhatia-Kissova; Resham Bhattacharya; Sujoy Bhattacharya; Shalmoli Bhattacharyya; Md Shenuarin Bhuiyan; Sujit Kumar Bhutia; Lanrong Bi; Xiaolin Bi; Trevor J Biden; Krikor Bijian; Viktor A Billes; Nadine Binart; Claudia Bincoletto; Asa B Birgisdottir; Geir Bjorkoy; Gonzalo Blanco; Ana Blas-Garcia; Janusz Blasiak; Robert Blomgran; Klas Blomgren; Janice S Blum; Emilio Boada-Romero; Mirta Boban; Kathleen Boesze-Battaglia; Philippe Boeuf; Barry Boland; Pascale Bomont; Paolo Bonaldo; Srinivasa Reddy Bonam; Laura Bonfili; Juan S Bonifacino; Brian A Boone; Martin D Bootman; Matteo Bordi; Christoph Borner; Beat C Bornhauser; Gautam Borthakur; Jürgen Bosch; Santanu Bose; Luis M Botana; Juan Botas; Chantal M Boulanger; Michael E Boulton; Mathieu Bourdenx; Benjamin Bourgeois; Nollaig M Bourke; Guilhem Bousquet; Patricia Boya; Peter V Bozhkov; Luiz H M Bozi; Tolga O Bozkurt; Doug E Brackney; Christian H Brandts; Ralf J Braun; Gerhard H Braus; Roberto Bravo-Sagua; José M Bravo-San Pedro; Patrick Brest; Marie-Agnès Bringer; Alfredo Briones-Herrera; V Courtney Broaddus; Peter Brodersen; Jeffrey L Brodsky; Steven L Brody; Paola G Bronson; Jeff M Bronstein; Carolyn N Brown; Rhoderick E Brown; Patricia C Brum; John H Brumell; Nicola Brunetti-Pierri; Daniele Bruno; Robert J Bryson-Richardson; Cecilia Bucci; Carmen Buchrieser; Marta Bueno; Laura Elisa Buitrago-Molina; Simone Buraschi; Shilpa Buch; J Ross Buchan; Erin M Buckingham; Hikmet Budak; Mauricio Budini; Geert Bultynck; Florin Burada; Joseph R Burgoyne; M Isabel Burón; Victor Bustos; Sabrina Büttner; Elena Butturini; Aaron Byrd; Isabel Cabas; Sandra Cabrera-Benitez; Ken Cadwell; Jingjing Cai; Lu Cai; Qian Cai; Montserrat Cairó; Jose A Calbet; Guy A Caldwell; Kim A Caldwell; Jarrod A Call; Riccardo Calvani; Ana C Calvo; Miguel Calvo-Rubio Barrera; Niels Os Camara; Jacques H Camonis; Nadine Camougrand; Michelangelo Campanella; Edward M Campbell; François-Xavier Campbell-Valois; Silvia Campello; Ilaria Campesi; Juliane C Campos; Olivier Camuzard; Jorge Cancino; Danilo Candido de Almeida; Laura Canesi; Isabella Caniggia; Barbara Canonico; Carles Cantí; Bin Cao; Michele Caraglia; Beatriz Caramés; Evie H Carchman; Elena Cardenal-Muñoz; Cesar Cardenas; Luis Cardenas; Sandra M Cardoso; Jennifer S Carew; Georges F Carle; Gillian Carleton; Silvia Carloni; Didac Carmona-Gutierrez; Leticia A Carneiro; Oliana Carnevali; Julian M Carosi; Serena Carra; Alice Carrier; Lucie Carrier; Bernadette Carroll; A Brent Carter; Andreia Neves Carvalho; Magali Casanova; Caty Casas; Josefina Casas; Chiara Cassioli; Eliseo F Castillo; Karen Castillo; Sonia Castillo-Lluva; Francesca Castoldi; Marco Castori; Ariel F Castro; Margarida Castro-Caldas; Javier Castro-Hernandez; Susana Castro-Obregon; Sergio D Catz; Claudia Cavadas; Federica Cavaliere; Gabriella Cavallini; Maria Cavinato; Maria L Cayuela; Paula Cebollada Rica; Valentina Cecarini; Francesco Cecconi; Marzanna Cechowska-Pasko; Simone Cenci; Victòria Ceperuelo-Mallafré; João J Cerqueira; Janete M Cerutti; Davide Cervia; Vildan Bozok Cetintas; Silvia Cetrullo; Han-Jung Chae; Andrei S Chagin; Chee-Yin Chai; Gopal Chakrabarti; Oishee Chakrabarti; Tapas Chakraborty; Trinad Chakraborty; Mounia Chami; Georgios Chamilos; David W Chan; Edmond Y W Chan; Edward D Chan; H Y Edwin Chan; Helen H Chan; Hung Chan; Matthew T V Chan; Yau Sang Chan; Partha K Chandra; Chih-Peng Chang; Chunmei Chang; Hao-Chun Chang; Kai Chang; Jie Chao; Tracey Chapman; Nicolas Charlet-Berguerand; Samrat Chatterjee; Shail K Chaube; Anu Chaudhary; Santosh Chauhan; Edward Chaum; Frédéric Checler; Michael E Cheetham; Chang-Shi Chen; Guang-Chao Chen; Jian-Fu Chen; Liam L Chen; Leilei Chen; Lin Chen; Mingliang Chen; Mu-Kuan Chen; Ning Chen; Quan Chen; Ruey-Hwa Chen; Shi Chen; Wei Chen; Weiqiang Chen; Xin-Ming Chen; Xiong-Wen Chen; Xu Chen; Yan Chen; Ye-Guang Chen; Yingyu Chen; Yongqiang Chen; Yu-Jen Chen; Yue-Qin Chen; Zhefan Stephen Chen; Zhi Chen; Zhi-Hua Chen; Zhijian J Chen; Zhixiang Chen; Hanhua Cheng; Jun Cheng; Shi-Yuan Cheng; Wei Cheng; Xiaodong Cheng; Xiu-Tang Cheng; Yiyun Cheng; Zhiyong Cheng; Zhong Chen; Heesun Cheong; Jit Kong Cheong; Boris V Chernyak; Sara Cherry; Chi Fai Randy Cheung; Chun Hei Antonio Cheung; King-Ho Cheung; Eric Chevet; Richard J Chi; Alan Kwok Shing Chiang; Ferdinando Chiaradonna; Roberto Chiarelli; Mario Chiariello; Nathalia Chica; Susanna Chiocca; Mario Chiong; Shih-Hwa Chiou; Abhilash I Chiramel; Valerio Chiurchiù; Dong-Hyung Cho; Seong-Kyu Choe; Augustine M K Choi; Mary E Choi; Kamalika Roy Choudhury; Norman S Chow; Charleen T Chu; Jason P Chua; John Jia En Chua; Hyewon Chung; Kin Pan Chung; Seockhoon Chung; So-Hyang Chung; Yuen-Li Chung; Valentina Cianfanelli; Iwona A Ciechomska; Mariana Cifuentes; Laura Cinque; Sebahattin Cirak; Mara Cirone; Michael J Clague; Robert Clarke; Emilio Clementi; Eliana M Coccia; Patrice Codogno; Ehud Cohen; Mickael M Cohen; Tania Colasanti; Fiorella Colasuonno; Robert A Colbert; Anna Colell; Miodrag Čolić; Nuria S Coll; Mark O Collins; María I Colombo; Daniel A Colón-Ramos; Lydie Combaret; Sergio Comincini; Márcia R Cominetti; Antonella Consiglio; Andrea Conte; Fabrizio Conti; Viorica Raluca Contu; Mark R Cookson; Kevin M Coombs; Isabelle Coppens; Maria Tiziana Corasaniti; Dale P Corkery; Nils Cordes; Katia Cortese; Maria do Carmo Costa; Sarah Costantino; Paola Costelli; Ana Coto-Montes; Peter J Crack; Jose L Crespo; Alfredo Criollo; Valeria Crippa; Riccardo Cristofani; Tamas Csizmadia; Antonio Cuadrado; Bing Cui; Jun Cui; Yixian Cui; Yong Cui; Emmanuel Culetto; Andrea C Cumino; Andrey V Cybulsky; Mark J Czaja; Stanislaw J Czuczwar; Stefania D'Adamo; Marcello D'Amelio; Daniela D'Arcangelo; Andrew C D'Lugos; Gabriella D'Orazi; James A da Silva; Hormos Salimi Dafsari; Ruben K Dagda; Yasin Dagdas; Maria Daglia; Xiaoxia Dai; Yun Dai; Yuyuan Dai; Jessica Dal Col; Paul Dalhaimer; Luisa Dalla Valle; Tobias Dallenga; Guillaume Dalmasso; Markus Damme; Ilaria Dando; Nico P Dantuma; April L Darling; Hiranmoy Das; Srinivasan Dasarathy; Santosh K Dasari; Srikanta Dash; Oliver Daumke; Adrian N Dauphinee; Jeffrey S Davies; Valeria A Dávila; Roger J Davis; Tanja Davis; Sharadha Dayalan Naidu; Francesca De Amicis; Karolien De Bosscher; Francesca De Felice; Lucia De Franceschi; Chiara De Leonibus; Mayara G de Mattos Barbosa; Guido R Y De Meyer; Angelo De Milito; Cosimo De Nunzio; Clara De Palma; Mauro De Santi; Claudio De Virgilio; Daniela De Zio; Jayanta Debnath; Brian J DeBosch; Jean-Paul Decuypere; Mark A Deehan; Gianluca Deflorian; James DeGregori; Benjamin Dehay; Gabriel Del Rio; Joe R Delaney; Lea M D Delbridge; Elizabeth Delorme-Axford; M Victoria Delpino; Francesca Demarchi; Vilma Dembitz; Nicholas D Demers; Hongbin Deng; Zhiqiang Deng; Joern Dengjel; Paul Dent; Donna Denton; Melvin L DePamphilis; Channing J Der; Vojo Deretic; Albert Descoteaux; Laura Devis; Sushil Devkota; Olivier Devuyst; Grant Dewson; Mahendiran Dharmasivam; Rohan Dhiman; Diego di Bernardo; Manlio Di Cristina; Fabio Di Domenico; Pietro Di Fazio; Alessio Di Fonzo; Giovanni Di Guardo; Gianni M Di Guglielmo; Luca Di Leo; Chiara Di Malta; Alessia Di Nardo; Martina Di Rienzo; Federica Di Sano; George Diallinas; Jiajie Diao; Guillermo Diaz-Araya; Inés Díaz-Laviada; Jared M Dickinson; Marc Diederich; Mélanie Dieudé; Ivan Dikic; Shiping Ding; Wen-Xing Ding; Luciana Dini; Jelena Dinić; Miroslav Dinic; Albena T Dinkova-Kostova; Marc S Dionne; Jörg H W Distler; Abhinav Diwan; Ian M C Dixon; Mojgan Djavaheri-Mergny; Ina Dobrinski; Oxana Dobrovinskaya; Radek Dobrowolski; Renwick C J Dobson; Jelena Đokić; Serap Dokmeci Emre; Massimo Donadelli; Bo Dong; Xiaonan Dong; Zhiwu Dong; Gerald W Dorn Ii; Volker Dotsch; Huan Dou; Juan Dou; Moataz Dowaidar; Sami Dridi; Liat Drucker; Ailian Du; Caigan Du; Guangwei Du; Hai-Ning Du; Li-Lin Du; André du Toit; Shao-Bin Duan; Xiaoqiong Duan; Sónia P Duarte; Anna Dubrovska; Elaine A Dunlop; Nicolas Dupont; Raúl V Durán; Bilikere S Dwarakanath; Sergey A Dyshlovoy; Darius Ebrahimi-Fakhari; Leopold Eckhart; Charles L Edelstein; Thomas Efferth; Eftekhar Eftekharpour; Ludwig Eichinger; Nabil Eid; Tobias Eisenberg; N Tony Eissa; Sanaa Eissa; Miriam Ejarque; Abdeljabar El Andaloussi; Nazira El-Hage; Shahenda El-Naggar; Anna Maria Eleuteri; Eman S El-Shafey; Mohamed Elgendy; Aristides G Eliopoulos; María M Elizalde; Philip M Elks; Hans-Peter Elsasser; Eslam S Elsherbiny; Brooke M Emerling; N C Tolga Emre; Christina H Eng; Nikolai Engedal; Anna-Mart Engelbrecht; Agnete S T Engelsen; Jorrit M Enserink; Ricardo Escalante; Audrey Esclatine; Mafalda Escobar-Henriques; Eeva-Liisa Eskelinen; Lucile Espert; Makandjou-Ola Eusebio; Gemma Fabrias; Cinzia Fabrizi; Antonio Facchiano; Francesco Facchiano; Bengt Fadeel; Claudio Fader; Alex C Faesen; W Douglas Fairlie; Alberto Falcó; Bjorn H Falkenburger; Daping Fan; Jie Fan; Yanbo Fan; Evandro F Fang; Yanshan Fang; Yognqi Fang; Manolis Fanto; Tamar Farfel-Becker; Mathias Faure; Gholamreza Fazeli; Anthony O Fedele; Arthur M Feldman; Du Feng; Jiachun Feng; Lifeng Feng; Yibin Feng; Yuchen Feng; Wei Feng; Thais Fenz Araujo; Thomas A Ferguson; Álvaro F Fernández; Jose C Fernandez-Checa; Sonia Fernández-Veledo; Alisdair R Fernie; Anthony W Ferrante; Alessandra Ferraresi; Merari F Ferrari; Julio C B Ferreira; Susan Ferro-Novick; Antonio Figueras; Riccardo Filadi; Nicoletta Filigheddu; Eduardo Filippi-Chiela; Giuseppe Filomeni; Gian Maria Fimia; Vittorio Fineschi; Francesca Finetti; Steven Finkbeiner; Edward A Fisher; Paul B Fisher; Flavio Flamigni; Steven J Fliesler; Trude H Flo; Ida Florance; Oliver Florey; Tullio Florio; Erika Fodor; Carlo Follo; Edward A Fon; Antonella Forlino; Francesco Fornai; Paola Fortini; Anna Fracassi; Alessandro Fraldi; Brunella Franco; Rodrigo Franco; Flavia Franconi; Lisa B Frankel; Scott L Friedman; Leopold F Fröhlich; Gema Frühbeck; Jose M Fuentes; Yukio Fujiki; Naonobu Fujita; Yuuki Fujiwara; Mitsunori Fukuda; Simone Fulda; Luc Furic; Norihiko Furuya; Carmela Fusco; Michaela U Gack; Lidia Gaffke; Sehamuddin Galadari; Alessia Galasso; Maria F Galindo; Sachith Gallolu Kankanamalage; Lorenzo Galluzzi; Vincent Galy; Noor Gammoh; Boyi Gan; Ian G Ganley; Feng Gao; Hui Gao; Minghui Gao; Ping Gao; Shou-Jiang Gao; Wentao Gao; Xiaobo Gao; Ana Garcera; Maria Noé Garcia; Verónica E Garcia; Francisco García-Del Portillo; Vega Garcia-Escudero; Aracely Garcia-Garcia; Marina Garcia-Macia; Diana García-Moreno; Carmen Garcia-Ruiz; Patricia García-Sanz; Abhishek D Garg; Ricardo Gargini; Tina Garofalo; Robert F Garry; Nils C Gassen; Damian Gatica; Liang Ge; Wanzhong Ge; Ruth Geiss-Friedlander; Cecilia Gelfi; Pascal Genschik; Ian E Gentle; Valeria Gerbino; Christoph Gerhardt; Kyla Germain; Marc Germain; David A Gewirtz; Elham Ghasemipour Afshar; Saeid Ghavami; Alessandra Ghigo; Manosij Ghosh; Georgios Giamas; Claudia Giampietri; Alexandra Giatromanolaki; Gary E Gibson; Spencer B Gibson; Vanessa Ginet; Edward Giniger; Carlotta Giorgi; Henrique Girao; Stephen E Girardin; Mridhula Giridharan; Sandy Giuliano; Cecilia Giulivi; Sylvie Giuriato; Julien Giustiniani; Alexander Gluschko; Veit Goder; Alexander Goginashvili; Jakub Golab; David C Goldstone; Anna Golebiewska; Luciana R Gomes; Rodrigo Gomez; Rubén Gómez-Sánchez; Maria Catalina Gomez-Puerto; Raquel Gomez-Sintes; Qingqiu Gong; Felix M Goni; Javier González-Gallego; Tomas Gonzalez-Hernandez; Rosa A Gonzalez-Polo; Jose A Gonzalez-Reyes; Patricia González-Rodríguez; Ing Swie Goping; Marina S Gorbatyuk; Nikolai V Gorbunov; Kıvanç Görgülü; Roxana M Gorojod; Sharon M Gorski; Sandro Goruppi; Cecilia Gotor; Roberta A Gottlieb; Illana Gozes; Devrim Gozuacik; Martin Graef; Markus H Gräler; Veronica Granatiero; Daniel Grasso; Joshua P Gray; Douglas R Green; Alexander Greenhough; Stephen L Gregory; Edward F Griffin; Mark W Grinstaff; Frederic Gros; Charles Grose; Angelina S Gross; Florian Gruber; Paolo Grumati; Tilman Grune; Xueyan Gu; Jun-Lin Guan; Carlos M Guardia; Kishore Guda; Flora Guerra; Consuelo Guerri; Prasun Guha; Carlos Guillén; Shashi Gujar; Anna Gukovskaya; Ilya Gukovsky; Jan Gunst; Andreas Günther; Anyonya R Guntur; Chuanyong Guo; Chun Guo; Hongqing Guo; Lian-Wang Guo; Ming Guo; Pawan Gupta; Shashi Kumar Gupta; Swapnil Gupta; Veer Bala Gupta; Vivek Gupta; Asa B Gustafsson; David D Gutterman; Ranjitha H B; Annakaisa Haapasalo; James E Haber; Aleksandra Hać; Shinji Hadano; Anders J Hafrén; Mansour Haidar; Belinda S Hall; Gunnel Halldén; Anne Hamacher-Brady; Andrea Hamann; Maho Hamasaki; Weidong Han; Malene Hansen; Phyllis I Hanson; Zijian Hao; Masaru Harada; Ljubica Harhaji-Trajkovic; Nirmala Hariharan; Nigil Haroon; James Harris; Takafumi Hasegawa; Noor Hasima Nagoor; Jeffrey A Haspel; Volker Haucke; Wayne D Hawkins; Bruce A Hay; Cole M Haynes; Soren B Hayrabedyan; Thomas S Hays; Congcong He; Qin He; Rong-Rong He; You-Wen He; Yu-Ying He; Yasser Heakal; Alexander M Heberle; J Fielding Hejtmancik; Gudmundur Vignir Helgason; Vanessa Henkel; Marc Herb; Alexander Hergovich; Anna Herman-Antosiewicz; Agustín Hernández; Carlos Hernandez; Sergio Hernandez-Diaz; Virginia Hernandez-Gea; Amaury Herpin; Judit Herreros; Javier H Hervás; Daniel Hesselson; Claudio Hetz; Volker T Heussler; Yujiro Higuchi; Sabine Hilfiker; Joseph A Hill; William S Hlavacek; Emmanuel A Ho; Idy H T Ho; Philip Wing-Lok Ho; Shu-Leong Ho; Wan Yun Ho; G Aaron Hobbs; Mark Hochstrasser; Peter H M Hoet; Daniel Hofius; Paul Hofman; Annika Höhn; Carina I Holmberg; Jose R Hombrebueno; Chang-Won Hong Yi-Ren Hong; Lora V Hooper; Thorsten Hoppe; Rastislav Horos; Yujin Hoshida; I-Lun Hsin; Hsin-Yun Hsu; Bing Hu; Dong Hu; Li-Fang Hu; Ming Chang Hu; Ronggui Hu; Wei Hu; Yu-Chen Hu; Zhuo-Wei Hu; Fang Hua; Jinlian Hua; Yingqi Hua; Chongmin Huan; Canhua Huang; Chuanshu Huang; Chuanxin Huang; Chunling Huang; Haishan Huang; Kun Huang; Michael L H Huang; Rui Huang; Shan Huang; Tianzhi Huang; Xing Huang; Yuxiang Jack Huang; Tobias B Huber; Virginie Hubert; Christian A Hubner; Stephanie M Hughes; William E Hughes; Magali Humbert; Gerhard Hummer; James H Hurley; Sabah Hussain; Salik Hussain; Patrick J Hussey; Martina Hutabarat; Hui-Yun Hwang; Seungmin Hwang; Antonio Ieni; Fumiyo Ikeda; Yusuke Imagawa; Yuzuru Imai; Carol Imbriano; Masaya Imoto; Denise M Inman; Ken Inoki; Juan Iovanna; Renato V Iozzo; Giuseppe Ippolito; Javier E Irazoqui; Pablo Iribarren; Mohd Ishaq; Makoto Ishikawa; Nestor Ishimwe; Ciro Isidoro; Nahed Ismail; Shohreh Issazadeh-Navikas; Eisuke Itakura; Daisuke Ito; Davor Ivankovic; Saška Ivanova; Anand Krishnan V Iyer; José M Izquierdo; Masanori Izumi; Marja Jäättelä; Majid Sakhi Jabir; William T Jackson; Nadia Jacobo-Herrera; Anne-Claire Jacomin; Elise Jacquin; Pooja Jadiya; Hartmut Jaeschke; Chinnaswamy Jagannath; Arjen J Jakobi; Johan Jakobsson; Bassam Janji; Pidder Jansen-Dürr; Patric J Jansson; Jonathan Jantsch; Sławomir Januszewski; Alagie Jassey; Steve Jean; Hélène Jeltsch-David; Pavla Jendelova; Andreas Jenny; Thomas E Jensen; Niels Jessen; Jenna L Jewell; Jing Ji; Lijun Jia; Rui Jia; Liwen Jiang; Qing Jiang; Richeng Jiang; Teng Jiang; Xuejun Jiang; Yu Jiang; Maria Jimenez-Sanchez; Eun-Jung Jin; Fengyan Jin; Hongchuan Jin; Li Jin; Luqi Jin; Meiyan Jin; Si Jin; Eun-Kyeong Jo; Carine Joffre; Terje Johansen; Gail V W Johnson; Simon A Johnston; Eija Jokitalo; Mohit Kumar Jolly; Leo A B Joosten; Joaquin Jordan; Bertrand Joseph; Dianwen Ju; Jeong-Sun Ju; Jingfang Ju; Esmeralda Juárez; Delphine Judith; Gábor Juhász; Youngsoo Jun; Chang Hwa Jung; Sung-Chul Jung; Yong Keun Jung; Heinz Jungbluth; Johannes Jungverdorben; Steffen Just; Kai Kaarniranta; Allen Kaasik; Tomohiro Kabuta; Daniel Kaganovich; Alon Kahana; Renate Kain; Shinjo Kajimura; Maria Kalamvoki; Manjula Kalia; Danuta S Kalinowski; Nina Kaludercic; Ioanna Kalvari; Joanna Kaminska; Vitaliy O Kaminskyy; Hiromitsu Kanamori; Keizo Kanasaki; Chanhee Kang; Rui Kang; Sang Sun Kang; Senthilvelrajan Kaniyappan; Tomotake Kanki; Thirumala-Devi Kanneganti; Anumantha G Kanthasamy; Arthi Kanthasamy; Marc Kantorow; Orsolya Kapuy; Michalis V Karamouzis; Md Razaul Karim; Parimal Karmakar; Rajesh G Katare; Masaru Kato; Stefan H E Kaufmann; Anu Kauppinen; Gur P Kaushal; Susmita Kaushik; Kiyoshi Kawasaki; Kemal Kazan; Po-Yuan Ke; Damien J Keating; Ursula Keber; John H Kehrl; Kate E Keller; Christian W Keller; Jongsook Kim Kemper; Candia M Kenific; Oliver Kepp; Stephanie Kermorgant; Andreas Kern; Robin Ketteler; Tom G Keulers; Boris Khalfin; Hany Khalil; Bilon Khambu; Shahid Y Khan; Vinoth Kumar Megraj Khandelwal; Rekha Khandia; Widuri Kho; Noopur V Khobrekar; Sataree Khuansuwan; Mukhran Khundadze; Samuel A Killackey; Dasol Kim; Deok Ryong Kim; Do-Hyung Kim; Dong-Eun Kim; Eun Young Kim; Eun-Kyoung Kim; Hak-Rim Kim; Hee-Sik Kim; Jeong Hun Kim; Jin Kyung Kim; Jin-Hoi Kim; Joungmok Kim; Ju Hwan Kim; Keun Il Kim; Peter K Kim; Seong-Jun Kim; Scot R Kimball; Adi Kimchi; Alec C Kimmelman; Tomonori Kimura; Matthew A King; Kerri J Kinghorn; Conan G Kinsey; Vladimir Kirkin; Lorrie A Kirshenbaum; Sergey L Kiselev; Shuji Kishi; Katsuhiko Kitamoto; Yasushi Kitaoka; Kaio Kitazato; Richard N Kitsis; Josef T Kittler; Ole Kjaerulff; Peter S Klein; Thomas Klopstock; Jochen Klucken; Helene Knævelsrud; Roland L Knorr; Ben C B Ko; Fred Ko; Jiunn-Liang Ko; Hotaka Kobayashi; Satoru Kobayashi; Ina Koch; Jan C Koch; Ulrich Koenig; Donat Kögel; Young Ho Koh; Masato Koike; Sepp D Kohlwein; Nur M Kocaturk; Masaaki Komatsu; Jeannette König; Toru Kono; Benjamin T Kopp; Tamas Korcsmaros; Gözde Korkmaz; Viktor I Korolchuk; Mónica Suárez Korsnes; Ali Koskela; Janaiah Kota; Yaichiro Kotake; Monica L Kotler; Yanjun Kou; Michael I Koukourakis; Evangelos Koustas; Attila L Kovacs; Tibor Kovács; Daisuke Koya; Tomohiro Kozako; Claudine Kraft; Dimitri Krainc; Helmut Krämer; Anna D Krasnodembskaya; Carole Kretz-Remy; Guido Kroemer; Nicholas T Ktistakis; Kazuyuki Kuchitsu; Sabine Kuenen; Lars Kuerschner; Thomas Kukar; Ajay Kumar; Ashok Kumar; Deepak Kumar; Dhiraj Kumar; Sharad Kumar; Shinji Kume; Caroline Kumsta; Chanakya N Kundu; Mondira Kundu; Ajaikumar B Kunnumakkara; Lukasz Kurgan; Tatiana G Kutateladze; Ozlem Kutlu; SeongAe Kwak; Ho Jeong Kwon; Taeg Kyu Kwon; Yong Tae Kwon; Irene Kyrmizi; Albert La Spada; Patrick Labonté; Sylvain Ladoire; Ilaria Laface; Frank Lafont; Diane C Lagace; Vikramjit Lahiri; Zhibing Lai; Angela S Laird; Aparna Lakkaraju; Trond Lamark; Sheng-Hui Lan; Ane Landajuela; Darius J R Lane; Jon D Lane; Charles H Lang; Carsten Lange; Ülo Langel; Rupert Langer; Pierre Lapaquette; Jocelyn Laporte; Nicholas F LaRusso; Isabel Lastres-Becker; Wilson Chun Yu Lau; Gordon W Laurie; Sergio Lavandero; Betty Yuen Kwan Law; Helen Ka-Wai Law; Rob Layfield; Weidong Le; Herve Le Stunff; Alexandre Y Leary; Jean-Jacques Lebrun; Lionel Y W Leck; Jean-Philippe Leduc-Gaudet; Changwook Lee; Chung-Pei Lee; Da-Hye Lee; Edward B Lee; Erinna F Lee; Gyun Min Lee; He-Jin Lee; Heung Kyu Lee; Jae Man Lee; Jason S Lee; Jin-A Lee; Joo-Yong Lee; Jun Hee Lee; Michael Lee; Min Goo Lee; Min Jae Lee; Myung-Shik Lee; Sang Yoon Lee; Seung-Jae Lee; Stella Y Lee; Sung Bae Lee; Won Hee Lee; Ying-Ray Lee; Yong-Ho Lee; Youngil Lee; Christophe Lefebvre; Renaud Legouis; Yu L Lei; Yuchen Lei; Sergey Leikin; Gerd Leitinger; Leticia Lemus; Shuilong Leng; Olivia Lenoir; Guido Lenz; Heinz Josef Lenz; Paola Lenzi; Yolanda León; Andréia M Leopoldino; Christoph Leschczyk; Stina Leskelä; Elisabeth Letellier; Chi-Ting Leung; Po Sing Leung; Jeremy S Leventhal; Beth Levine; Patrick A Lewis; Klaus Ley; Bin Li; Da-Qiang Li; Jianming Li; Jing Li; Jiong Li; Ke Li; Liwu Li; Mei Li; Min Li; Min Li; Ming Li; Mingchuan Li; Pin-Lan Li; Ming-Qing Li; Qing Li; Sheng Li; Tiangang Li; Wei Li; Wenming Li; Xue Li; Yi-Ping Li; Yuan Li; Zhiqiang Li; Zhiyong Li; Zhiyuan Li; Jiqin Lian; Chengyu Liang; Qiangrong Liang; Weicheng Liang; Yongheng Liang; YongTian Liang; Guanghong Liao; Lujian Liao; Mingzhi Liao; Yung-Feng Liao; Mariangela Librizzi; Pearl P Y Lie; Mary A Lilly; Hyunjung J Lim; Thania R R Lima; Federica Limana; Chao Lin; Chih-Wen Lin; Dar-Shong Lin; Fu-Cheng Lin; Jiandie D Lin; Kurt M Lin; Kwang-Huei Lin; Liang-Tzung Lin; Pei-Hui Lin; Qiong Lin; Shaofeng Lin; Su-Ju Lin; Wenyu Lin; Xueying Lin; Yao-Xin Lin; Yee-Shin Lin; Rafael Linden; Paula Lindner; Shuo-Chien Ling; Paul Lingor; Amelia K Linnemann; Yih-Cherng Liou; Marta M Lipinski; Saška Lipovšek; Vitor A Lira; Natalia Lisiak; Paloma B Liton; Chao Liu; Ching-Hsuan Liu; Chun-Feng Liu; Cui Hua Liu; Fang Liu; Hao Liu; Hsiao-Sheng Liu; Hua-Feng Liu; Huifang Liu; Jia Liu; Jing Liu; Julia Liu; Leyuan Liu; Longhua Liu; Meilian Liu; Qin Liu; Wei Liu; Wende Liu; Xiao-Hong Liu; Xiaodong Liu; Xingguo Liu; Xu Liu; Xuedong Liu; Yanfen Liu; Yang Liu; Yang Liu; Yueyang Liu; Yule Liu; J Andrew Livingston; Gerard Lizard; Jose M Lizcano; Senka Ljubojevic-Holzer; Matilde E LLeonart; David Llobet-Navàs; Alicia Llorente; Chih Hung Lo; Damián Lobato-Márquez; Qi Long; Yun Chau Long; Ben Loos; Julia A Loos; Manuela G López; Guillermo López-Doménech; José Antonio López-Guerrero; Ana T López-Jiménez; Óscar López-Pérez; Israel López-Valero; Magdalena J Lorenowicz; Mar Lorente; Peter Lorincz; Laura Lossi; Sophie Lotersztajn; Penny E Lovat; Jonathan F Lovell; Alenka Lovy; Péter Lőw; Guang Lu; Haocheng Lu; Jia-Hong Lu; Jin-Jian Lu; Mengji Lu; Shuyan Lu; Alessandro Luciani; John M Lucocq; Paula Ludovico; Micah A Luftig; Morten Luhr; Diego Luis-Ravelo; Julian J Lum; Liany Luna-Dulcey; Anders H Lund; Viktor K Lund; Jan D Lünemann; Patrick Lüningschrör; Honglin Luo; Rongcan Luo; Shouqing Luo; Zhi Luo; Claudio Luparello; Bernhard Lüscher; Luan Luu; Alex Lyakhovich; Konstantin G Lyamzaev; Alf Håkon Lystad; Lyubomyr Lytvynchuk; Alvin C Ma; Changle Ma; Mengxiao Ma; Ning-Fang Ma; Quan-Hong Ma; Xinliang Ma; Yueyun Ma; Zhenyi Ma; Ormond A MacDougald; Fernando Macian; Gustavo C MacIntosh; Jeffrey P MacKeigan; Kay F Macleod; Sandra Maday; Frank Madeo; Muniswamy Madesh; Tobias Madl; Julio Madrigal-Matute; Akiko Maeda; Yasuhiro Maejima; Marta Magarinos; Poornima Mahavadi; Emiliano Maiani; Kenneth Maiese; Panchanan Maiti; Maria Chiara Maiuri; Barbara Majello; Michael B Major; Elena Makareeva; Fayaz Malik; Karthik Mallilankaraman; Walter Malorni; Alina Maloyan; Najiba Mammadova; Gene Chi Wai Man; Federico Manai; Joseph D Mancias; Eva-Maria Mandelkow; Michael A Mandell; Angelo A Manfredi; Masoud H Manjili; Ravi Manjithaya; Patricio Manque; Bella B Manshian; Raquel Manzano; Claudia Manzoni; Kai Mao; Cinzia Marchese; Sandrine Marchetti; Anna Maria Marconi; Fabrizio Marcucci; Stefania Mardente; Olga A Mareninova; Marta Margeta; Muriel Mari; Sara Marinelli; Oliviero Marinelli; Guillermo Mariño; Sofia Mariotto; Richard S Marshall; Mark R Marten; Sascha Martens; Alexandre P J Martin; Katie R Martin; Sara Martin; Shaun Martin; Adrián Martín-Segura; Miguel A Martín-Acebes; Inmaculada Martin-Burriel; Marcos Martin-Rincon; Paloma Martin-Sanz; José A Martina; Wim Martinet; Aitor Martinez; Ana Martinez; Jennifer Martinez; Moises Martinez Velazquez; Nuria Martinez-Lopez; Marta Martinez-Vicente; Daniel O Martins; Joilson O Martins; Waleska K Martins; Tania Martins-Marques; Emanuele Marzetti; Shashank Masaldan; Celine Masclaux-Daubresse; Douglas G Mashek; Valentina Massa; Lourdes Massieu; Glenn R Masson; Laura Masuelli; Anatoliy I Masyuk; Tetyana V Masyuk; Paola Matarrese; Ander Matheu; Satoaki Matoba; Sachiko Matsuzaki; Pamela Mattar; Alessandro Matte; Domenico Mattoscio; José L Mauriz; Mario Mauthe; Caroline Mauvezin; Emanual Maverakis; Paola Maycotte; Johanna Mayer; Gianluigi Mazzoccoli; Cristina Mazzoni; Joseph R Mazzulli; Nami McCarty; Christine McDonald; Mitchell R McGill; Sharon L McKenna; BethAnn McLaughlin; Fionn McLoughlin; Mark A McNiven; Thomas G McWilliams; Fatima Mechta-Grigoriou; Tania Catarina Medeiros; Diego L Medina; Lynn A Megeney; Klara Megyeri; Maryam Mehrpour; Jawahar L Mehta; Alfred J Meijer; Annemarie H Meijer; Jakob Mejlvang; Alicia Meléndez; Annette Melk; Gonen Memisoglu; Alexandrina F Mendes; Delong Meng; Fei Meng; Tian Meng; Rubem Menna-Barreto; Manoj B Menon; Carol Mercer; Anne E Mercier; Jean-Louis Mergny; Adalberto Merighi; Seth D Merkley; Giuseppe Merla; Volker Meske; Ana Cecilia Mestre; Shree Padma Metur; Christian Meyer; Hemmo Meyer; Wenyi Mi; Jeanne Mialet-Perez; Junying Miao; Lucia Micale; Yasuo Miki; Enrico Milan; Małgorzata Milczarek; Dana L Miller; Samuel I Miller; Silke Miller; Steven W Millward; Ira Milosevic; Elena A Minina; Hamed Mirzaei; Hamid Reza Mirzaei; Mehdi Mirzaei; Amit Mishra; Nandita Mishra; Paras Kumar Mishra; Maja Misirkic Marjanovic; Roberta Misasi; Amit Misra; Gabriella Misso; Claire Mitchell; Geraldine Mitou; Tetsuji Miura; Shigeki Miyamoto; Makoto Miyazaki; Mitsunori Miyazaki; Taiga Miyazaki; Keisuke Miyazawa; Noboru Mizushima; Trine H Mogensen; Baharia Mograbi; Reza Mohammadinejad; Yasir Mohamud; Abhishek Mohanty; Sipra Mohapatra; Torsten Möhlmann; Asif Mohmmed; Anna Moles; Kelle H Moley; Maurizio Molinari; Vincenzo Mollace; Andreas Buch Møller; Bertrand Mollereau; Faustino Mollinedo; Costanza Montagna; Mervyn J Monteiro; Andrea Montella; L Ruth Montes; Barbara Montico; Vinod K Mony; Giacomo Monzio Compagnoni; Michael N Moore; Mohammad A Moosavi; Ana L Mora; Marina Mora; David Morales-Alamo; Rosario Moratalla; Paula I Moreira; Elena Morelli; Sandra Moreno; Daniel Moreno-Blas; Viviana Moresi; Benjamin Morga; Alwena H Morgan; Fabrice Morin; Hideaki Morishita; Orson L Moritz; Mariko Moriyama; Yuji Moriyasu; Manuela Morleo; Eugenia Morselli; Jose F Moruno-Manchon; Jorge Moscat; Serge Mostowy; Elisa Motori; Andrea Felinto Moura; Naima Moustaid-Moussa; Maria Mrakovcic; Gabriel Muciño-Hernández; Anupam Mukherjee; Subhadip Mukhopadhyay; Jean M Mulcahy Levy; Victoriano Mulero; Sylviane Muller; Christian Münch; Ashok Munjal; Pura Munoz-Canoves; Teresa Muñoz-Galdeano; Christian Münz; Tomokazu Murakawa; Claudia Muratori; Brona M Murphy; J Patrick Murphy; Aditya Murthy; Timo T Myöhänen; Indira U Mysorekar; Jennifer Mytych; Seyed Mohammad Nabavi; Massimo Nabissi; Péter Nagy; Jihoon Nah; Aimable Nahimana; Ichiro Nakagawa; Ken Nakamura; Hitoshi Nakatogawa; Shyam S Nandi; Meera Nanjundan; Monica Nanni; Gennaro Napolitano; Roberta Nardacci; Masashi Narita; Melissa Nassif; Ilana Nathan; Manabu Natsumeda; Ryno J Naude; Christin Naumann; Olaia Naveiras; Fatemeh Navid; Steffan T Nawrocki; Taras Y Nazarko; Francesca Nazio; Florentina Negoita; Thomas Neill; Amanda L Neisch; Luca M Neri; Mihai G Netea; Patrick Neubert; Thomas P Neufeld; Dietbert Neumann; Albert Neutzner; Phillip T Newton; Paul A Ney; Ioannis P Nezis; Charlene C W Ng; Tzi Bun Ng; Hang T T Nguyen; Long T Nguyen; Hong-Min Ni; Clíona Ní Cheallaigh; Zhenhong Ni; M Celeste Nicolao; Francesco Nicoli; Manuel Nieto-Diaz; Per Nilsson; Shunbin Ning; Rituraj Niranjan; Hiroshi Nishimune; Mireia Niso-Santano; Ralph A Nixon; Annalisa Nobili; Clevio Nobrega; Takeshi Noda; Uxía Nogueira-Recalde; Trevor M Nolan; Ivan Nombela; Ivana Novak; Beatriz Novoa; Takashi Nozawa; Nobuyuki Nukina; Carmen Nussbaum-Krammer; Jesper Nylandsted; Tracey R O'Donovan; Seónadh M O'Leary; Eyleen J O'Rourke; Mary P O'Sullivan; Timothy E O'Sullivan; Salvatore Oddo; Ina Oehme; Michinaga Ogawa; Eric Ogier-Denis; Margret H Ogmundsdottir; Besim Ogretmen; Goo Taeg Oh; Seon-Hee Oh; Young J Oh; Takashi Ohama; Yohei Ohashi; Masaki Ohmuraya; Vasileios Oikonomou; Rani Ojha; Koji Okamoto; Hitoshi Okazawa; Masahide Oku; Sara Oliván; Jorge M A Oliveira; Michael Ollmann; James A Olzmann; Shakib Omari; M Bishr Omary; Gizem Önal; Martin Ondrej; Sang-Bing Ong; Sang-Ging Ong; Anna Onnis; Juan A Orellana; Sara Orellana-Muñoz; Maria Del Mar Ortega-Villaizan; Xilma R Ortiz-Gonzalez; Elena Ortona; Heinz D Osiewacz; Abdel-Hamid K Osman; Rosario Osta; Marisa S Otegui; Kinya Otsu; Christiane Ott; Luisa Ottobrini; Jing-Hsiung James Ou; Tiago F Outeiro; Inger Oynebraten; Melek Ozturk; Gilles Pagès; Susanta Pahari; Marta Pajares; Utpal B Pajvani; Rituraj Pal; Simona Paladino; Nicolas Pallet; Michela Palmieri; Giuseppe Palmisano; Camilla Palumbo; Francesco Pampaloni; Lifeng Pan; Qingjun Pan; Wenliang Pan; Xin Pan; Ganna Panasyuk; Rahul Pandey; Udai B Pandey; Vrajesh Pandya; Francesco Paneni; Shirley Y Pang; Elisa Panzarini; Daniela L Papademetrio; Elena Papaleo; Daniel Papinski; Diana Papp; Eun Chan Park; Hwan Tae Park; Ji-Man Park; Jong-In Park; Joon Tae Park; Junsoo Park; Sang Chul Park; Sang-Youel Park; Abraham H Parola; Jan B Parys; Adrien Pasquier; Benoit Pasquier; João F Passos; Nunzia Pastore; Hemal H Patel; Daniel Patschan; Sophie Pattingre; Gustavo Pedraza-Alva; Jose Pedraza-Chaverri; Zully Pedrozo; Gang Pei; Jianming Pei; Hadas Peled-Zehavi; Joaquín M Pellegrini; Joffrey Pelletier; Miguel A Peñalva; Di Peng; Ying Peng; Fabio Penna; Maria Pennuto; Francesca Pentimalli; Cláudia Mf Pereira; Gustavo J S Pereira; Lilian C Pereira; Luis Pereira de Almeida; Nirma D Perera; Ángel Pérez-Lara; Ana B Perez-Oliva; María Esther Pérez-Pérez; Palsamy Periyasamy; Andras Perl; Cristiana Perrotta; Ida Perrotta; Richard G Pestell; Morten Petersen; Irina Petrache; Goran Petrovski; Thorsten Pfirrmann; Astrid S Pfister; Jennifer A Philips; Huifeng Pi; Anna Picca; Alicia M Pickrell; Sandy Picot; Giovanna M Pierantoni; Marina Pierdominici; Philippe Pierre; Valérie Pierrefite-Carle; Karolina Pierzynowska; Federico Pietrocola; Miroslawa Pietruczuk; Claudio Pignata; Felipe X Pimentel-Muiños; Mario Pinar; Roberta O Pinheiro; Ronit Pinkas-Kramarski; Paolo Pinton; Karolina Pircs; Sujan Piya; Paola Pizzo; Theo S Plantinga; Harald W Platta; Ainhoa Plaza-Zabala; Markus Plomann; Egor Y Plotnikov; Helene Plun-Favreau; Ryszard Pluta; Roger Pocock; Stefanie Pöggeler; Christian Pohl; Marc Poirot; Angelo Poletti; Marisa Ponpuak; Hana Popelka; Blagovesta Popova; Helena Porta; Soledad Porte Alcon; Eliana Portilla-Fernandez; Martin Post; Malia B Potts; Joanna Poulton; Ted Powers; Veena Prahlad; Tomasz K Prajsnar; Domenico Praticò; Rosaria Prencipe; Muriel Priault; Tassula Proikas-Cezanne; Vasilis J Promponas; Christopher G Proud; Rosa Puertollano; Luigi Puglielli; Thomas Pulinilkunnil; Deepika Puri; Rajat Puri; Julien Puyal; Xiaopeng Qi; Yongmei Qi; Wenbin Qian; Lei Qiang; Yu Qiu; Joe Quadrilatero; Jorge Quarleri; Nina Raben; Hannah Rabinowich; Debora Ragona; Michael J Ragusa; Nader Rahimi; Marveh Rahmati; Valeria Raia; Nuno Raimundo; Namakkal-Soorappan Rajasekaran; Sriganesh Ramachandra Rao; Abdelhaq Rami; Ignacio Ramírez-Pardo; David B Ramsden; Felix Randow; Pundi N Rangarajan; Danilo Ranieri; Hai Rao; Lang Rao; Rekha Rao; Sumit Rathore; J Arjuna Ratnayaka; Edward A Ratovitski; Palaniyandi Ravanan; Gloria Ravegnini; Swapan K Ray; Babak Razani; Vito Rebecca; Fulvio Reggiori; Anne Régnier-Vigouroux; Andreas S Reichert; David Reigada; Jan H Reiling; Theo Rein; Siegfried Reipert; Rokeya Sultana Rekha; Hongmei Ren; Jun Ren; Weichao Ren; Tristan Renault; Giorgia Renga; Karen Reue; Kim Rewitz; Bruna Ribeiro de Andrade Ramos; S Amer Riazuddin; Teresa M Ribeiro-Rodrigues; Jean-Ehrland Ricci; Romeo Ricci; Victoria Riccio; Des R Richardson; Yasuko Rikihisa; Makarand V Risbud; Ruth M Risueño; Konstantinos Ritis; Salvatore Rizza; Rosario Rizzuto; Helen C Roberts; Luke D Roberts; Katherine J Robinson; Maria Carmela Roccheri; Stephane Rocchi; George G Rodney; Tiago Rodrigues; Vagner Ramon Rodrigues Silva; Amaia Rodriguez; Ruth Rodriguez-Barrueco; Nieves Rodriguez-Henche; Humberto Rodriguez-Rocha; Jeroen Roelofs; Robert S Rogers; Vladimir V Rogov; Ana I Rojo; Krzysztof Rolka; Vanina Romanello; Luigina Romani; Alessandra Romano; Patricia S Romano; David Romeo-Guitart; Luis C Romero; Montserrat Romero; Joseph C Roney; Christopher Rongo; Sante Roperto; Mathias T Rosenfeldt; Philip Rosenstiel; Anne G Rosenwald; Kevin A Roth; Lynn Roth; Steven Roth; Kasper M A Rouschop; Benoit D Roussel; Sophie Roux; Patrizia Rovere-Querini; Ajit Roy; Aurore Rozieres; Diego Ruano; David C Rubinsztein; Maria P Rubtsova; Klaus Ruckdeschel; Christoph Ruckenstuhl; Emil Rudolf; Rüdiger Rudolf; Alessandra Ruggieri; Avnika Ashok Ruparelia; Paola Rusmini; Ryan R Russell; Gian Luigi Russo; Maria Russo; Rossella Russo; Oxana O Ryabaya; Kevin M Ryan; Kwon-Yul Ryu; Maria Sabater-Arcis; Ulka Sachdev; Michael Sacher; Carsten Sachse; Abhishek Sadhu; Junichi Sadoshima; Nathaniel Safren; Paul Saftig; Antonia P Sagona; Gaurav Sahay; Amirhossein Sahebkar; Mustafa Sahin; Ozgur Sahin; Sumit Sahni; Nayuta Saito; Shigeru Saito; Tsunenori Saito; Ryohei Sakai; Yasuyoshi Sakai; Jun-Ichi Sakamaki; Kalle Saksela; Gloria Salazar; Anna Salazar-Degracia; Ghasem H Salekdeh; Ashok K Saluja; Belém Sampaio-Marques; Maria Cecilia Sanchez; Jose A Sanchez-Alcazar; Victoria Sanchez-Vera; Vanessa Sancho-Shimizu; J Thomas Sanderson; Marco Sandri; Stefano Santaguida; Laura Santambrogio; Magda M Santana; Giorgio Santoni; Alberto Sanz; Pascual Sanz; Shweta Saran; Marco Sardiello; Timothy J Sargeant; Apurva Sarin; Chinmoy Sarkar; Sovan Sarkar; Maria-Rosa Sarrias; Surajit Sarkar; Dipanka Tanu Sarmah; Jaakko Sarparanta; Aishwarya Sathyanarayan; Ranganayaki Sathyanarayanan; K Matthew Scaglione; Francesca Scatozza; Liliana Schaefer; Zachary T Schafer; Ulrich E Schaible; Anthony H V Schapira; Michael Scharl; Hermann M Schatzl; Catherine H Schein; Wiep Scheper; David Scheuring; Maria Vittoria Schiaffino; Monica Schiappacassi; Rainer Schindl; Uwe Schlattner; Oliver Schmidt; Roland Schmitt; Stephen D Schmidt; Ingo Schmitz; Eran Schmukler; Anja Schneider; Bianca E Schneider; Romana Schober; Alejandra C Schoijet; Micah B Schott; Michael Schramm; Bernd Schröder; Kai Schuh; Christoph Schüller; Ryan J Schulze; Lea Schürmanns; Jens C Schwamborn; Melanie Schwarten; Filippo Scialo; Sebastiano Sciarretta; Melanie J Scott; Kathleen W Scotto; A Ivana Scovassi; Andrea Scrima; Aurora Scrivo; David Sebastian; Salwa Sebti; Simon Sedej; Laura Segatori; Nava Segev; Per O Seglen; Iban Seiliez; Ekihiro Seki; Scott B Selleck; Frank W Sellke; Joshua T Selsby; Michael Sendtner; Serif Senturk; Elena Seranova; Consolato Sergi; Ruth Serra-Moreno; Hiromi Sesaki; Carmine Settembre; Subba Rao Gangi Setty; Gianluca Sgarbi; Ou Sha; John J Shacka; Javeed A Shah; Dantong Shang; Changshun Shao; Feng Shao; Soroush Sharbati; Lisa M Sharkey; Dipali Sharma; Gaurav Sharma; Kulbhushan Sharma; Pawan Sharma; Surendra Sharma; Han-Ming Shen; Hongtao Shen; Jiangang Shen; Ming Shen; Weili Shen; Zheni Shen; Rui Sheng; Zhi Sheng; Zu-Hang Sheng; Jianjian Shi; Xiaobing Shi; Ying-Hong Shi; Kahori Shiba-Fukushima; Jeng-Jer Shieh; Yohta Shimada; Shigeomi Shimizu; Makoto Shimozawa; Takahiro Shintani; Christopher J Shoemaker; Shahla Shojaei; Ikuo Shoji; Bhupendra V Shravage; Viji Shridhar; Chih-Wen Shu; Hong-Bing Shu; Ke Shui; Arvind K Shukla; Timothy E Shutt; Valentina Sica; Aleem Siddiqui; Amanda Sierra; Virginia Sierra-Torre; Santiago Signorelli; Payel Sil; Bruno J de Andrade Silva; Johnatas D Silva; Eduardo Silva-Pavez; Sandrine Silvente-Poirot; Rachel E Simmonds; Anna Katharina Simon; Hans-Uwe Simon; Matias Simons; Anurag Singh; Lalit P Singh; Rajat Singh; Shivendra V Singh; Shrawan K Singh; Sudha B Singh; Sunaina Singh; Surinder Pal Singh; Debasish Sinha; Rohit Anthony Sinha; Sangita Sinha; Agnieszka Sirko; Kapil Sirohi; Efthimios L Sivridis; Panagiotis Skendros; Aleksandra Skirycz; Iva Slaninová; Soraya S Smaili; Andrei Smertenko; Matthew D Smith; Stefaan J Soenen; Eun Jung Sohn; Sophia P M Sok; Giancarlo Solaini; Thierry Soldati; Scott A Soleimanpour; Rosa M Soler; Alexei Solovchenko; Jason A Somarelli; Avinash Sonawane; Fuyong Song; Hyun Kyu Song; Ju-Xian Song; Kunhua Song; Zhiyin Song; Leandro R Soria; Maurizio Sorice; Alexander A Soukas; Sandra-Fausia Soukup; Diana Sousa; Nadia Sousa; Paul A Spagnuolo; Stephen A Spector; M M Srinivas Bharath; Daret St Clair; Venturina Stagni; Leopoldo Staiano; Clint A Stalnecker; Metodi V Stankov; Peter B Stathopulos; Katja Stefan; Sven Marcel Stefan; Leonidas Stefanis; Joan S Steffan; Alexander Steinkasserer; Harald Stenmark; Jared Sterneckert; Craig Stevens; Veronika Stoka; Stephan Storch; Björn Stork; Flavie Strappazzon; Anne Marie Strohecker; Dwayne G Stupack; Huanxing Su; Ling-Yan Su; Longxiang Su; Ana M Suarez-Fontes; Carlos S Subauste; Selvakumar Subbian; Paula V Subirada; Ganapasam Sudhandiran; Carolyn M Sue; Xinbing Sui; Corey Summers; Guangchao Sun; Jun Sun; Kang Sun; Meng-Xiang Sun; Qiming Sun; Yi Sun; Zhongjie Sun; Karen K S Sunahara; Eva Sundberg; Katalin Susztak; Peter Sutovsky; Hidekazu Suzuki; Gary Sweeney; J David Symons; Stephen Cho Wing Sze; Nathaniel J Szewczyk; Anna Tabęcka-Łonczynska; Claudio Tabolacci; Frank Tacke; Heinrich Taegtmeyer; Marco Tafani; Mitsuo Tagaya; Haoran Tai; Stephen W G Tait; Yoshinori Takahashi; Szabolcs Takats; Priti Talwar; Chit Tam; Shing Yau Tam; Davide Tampellini; Atsushi Tamura; Chong Teik Tan; Eng-King Tan; Ya-Qin Tan; Masaki Tanaka; Motomasa Tanaka; Daolin Tang; Jingfeng Tang; Tie-Shan Tang; Isei Tanida; Zhipeng Tao; Mohammed Taouis; Lars Tatenhorst; Nektarios Tavernarakis; Allen Taylor; Gregory A Taylor; Joan M Taylor; Elena Tchetina; Andrew R Tee; Irmgard Tegeder; David Teis; Natercia Teixeira; Fatima Teixeira-Clerc; Kumsal A Tekirdag; Tewin Tencomnao; Sandra Tenreiro; Alexei V Tepikin; Pilar S Testillano; Gianluca Tettamanti; Pierre-Louis Tharaux; Kathrin Thedieck; Arvind A Thekkinghat; Stefano Thellung; Josephine W Thinwa; V P Thirumalaikumar; Sufi Mary Thomas; Paul G Thomes; Andrew Thorburn; Lipi Thukral; Thomas Thum; Michael Thumm; Ling Tian; Ales Tichy; Andreas Till; Vincent Timmerman; Vladimir I Titorenko; Sokol V Todi; Krassimira Todorova; Janne M Toivonen; Luana Tomaipitinca; Dhanendra Tomar; Cristina Tomas-Zapico; Sergej Tomić; Benjamin Chun-Kit Tong; Chao Tong; Xin Tong; Sharon A Tooze; Maria L Torgersen; Satoru Torii; Liliana Torres-López; Alicia Torriglia; Christina G Towers; Roberto Towns; Shinya Toyokuni; Vladimir Trajkovic; Donatella Tramontano; Quynh-Giao Tran; Leonardo H Travassos; Charles B Trelford; Shirley Tremel; Ioannis P Trougakos; Betty P Tsao; Mario P Tschan; Hung-Fat Tse; Tak Fu Tse; Hitoshi Tsugawa; Andrey S Tsvetkov; David A Tumbarello; Yasin Tumtas; María J Tuñón; Sandra Turcotte; Boris Turk; Vito Turk; Bradley J Turner; Richard I Tuxworth; Jessica K Tyler; Elena V Tyutereva; Yasuo Uchiyama; Aslihan Ugun-Klusek; Holm H Uhlig; Marzena Ułamek-Kozioł; Ilya V Ulasov; Midori Umekawa; Christian Ungermann; Rei Unno; Sylvie Urbe; Elisabet Uribe-Carretero; Suayib Üstün; Vladimir N Uversky; Thomas Vaccari; Maria I Vaccaro; Björn F Vahsen; Helin Vakifahmetoglu-Norberg; Rut Valdor; Maria J Valente; Ayelén Valko; Richard B Vallee; Angela M Valverde; Greet Van den Berghe; Stijn van der Veen; Luc Van Kaer; Jorg van Loosdregt; Sjoerd J L van Wijk; Wim Vandenberghe; Ilse Vanhorebeek; Marcos A Vannier-Santos; Nicola Vannini; M Cristina Vanrell; Chiara Vantaggiato; Gabriele Varano; Isabel Varela-Nieto; Máté Varga; M Helena Vasconcelos; Somya Vats; Demetrios G Vavvas; Ignacio Vega-Naredo; Silvia Vega-Rubin-de-Celis; Guillermo Velasco; Ariadna P Velázquez; Tibor Vellai; Edo Vellenga; Francesca Velotti; Mireille Verdier; Panayotis Verginis; Isabelle Vergne; Paul Verkade; Manish Verma; Patrik Verstreken; Tim Vervliet; Jörg Vervoorts; Alexandre T Vessoni; Victor M Victor; Michel Vidal; Chiara Vidoni; Otilia V Vieira; Richard D Vierstra; Sonia Viganó; Helena Vihinen; Vinoy Vijayan; Miquel Vila; Marçal Vilar; José M Villalba; Antonio Villalobo; Beatriz Villarejo-Zori; Francesc Villarroya; Joan Villarroya; Olivier Vincent; Cecile Vindis; Christophe Viret; Maria Teresa Viscomi; Dora Visnjic; Ilio Vitale; David J Vocadlo; Olga V Voitsekhovskaja; Cinzia Volonté; Mattia Volta; Marta Vomero; Clarissa Von Haefen; Marc A Vooijs; Wolfgang Voos; Ljubica Vucicevic; Richard Wade-Martins; Satoshi Waguri; Kenrick A Waite; Shuji Wakatsuki; David W Walker; Mark J Walker; Simon A Walker; Jochen Walter; Francisco G Wandosell; Bo Wang; Chao-Yung Wang; Chen Wang; Chenran Wang; Chenwei Wang; Cun-Yu Wang; Dong Wang; Fangyang Wang; Feng Wang; Fengming Wang; Guansong Wang; Han Wang; Hao Wang; Hexiang Wang; Hong-Gang Wang; Jianrong Wang; Jigang Wang; Jiou Wang; Jundong Wang; Kui Wang; Lianrong Wang; Liming Wang; Maggie Haitian Wang; Meiqing Wang; Nanbu Wang; Pengwei Wang; Peipei Wang; Ping Wang; Ping Wang; Qing Jun Wang; Qing Wang; Qing Kenneth Wang; Qiong A Wang; Wen-Tao Wang; Wuyang Wang; Xinnan Wang; Xuejun Wang; Yan Wang; Yanchang Wang; Yanzhuang Wang; Yen-Yun Wang; Yihua Wang; Yipeng Wang; Yu Wang; Yuqi Wang; Zhe Wang; Zhenyu Wang; Zhouguang Wang; Gary Warnes; Verena Warnsmann; Hirotaka Watada; Eizo Watanabe; Maxinne Watchon; Anna Wawrzyńska; Timothy E Weaver; Grzegorz Wegrzyn; Ann M Wehman; Huafeng Wei; Lei Wei; Taotao Wei; Yongjie Wei; Oliver H Weiergräber; Conrad C Weihl; Günther Weindl; Ralf Weiskirchen; Alan Wells; Runxia H Wen; Xin Wen; Antonia Werner; Beatrice Weykopf; Sally P Wheatley; J Lindsay Whitton; Alexander J Whitworth; Katarzyna Wiktorska; Manon E Wildenberg; Tom Wileman; Simon Wilkinson; Dieter Willbold; Brett Williams; Robin S B Williams; Roger L Williams; Peter R Williamson; Richard A Wilson; Beate Winner; Nathaniel J Winsor; Steven S Witkin; Harald Wodrich; Ute Woehlbier; Thomas Wollert; Esther Wong; Jack Ho Wong; Richard W Wong; Vincent Kam Wai Wong; W Wei-Lynn Wong; An-Guo Wu; Chengbiao Wu; Jian Wu; Junfang Wu; Kenneth K Wu; Min Wu; Shan-Ying Wu; Shengzhou Wu; Shu-Yan Wu; Shufang Wu; William K K Wu; Xiaohong Wu; Xiaoqing Wu; Yao-Wen Wu; Yihua Wu; Ramnik J Xavier; Hongguang Xia; Lixin Xia; Zhengyuan Xia; Ge Xiang; Jin Xiang; Mingliang Xiang; Wei Xiang; Bin Xiao; Guozhi Xiao; Hengyi Xiao; Hong-Tao Xiao; Jian Xiao; Lan Xiao; Shi Xiao; Yin Xiao; Baoming Xie; Chuan-Ming Xie; Min Xie; Yuxiang Xie; Zhiping Xie; Zhonglin Xie; Maria Xilouri; Congfeng Xu; En Xu; Haoxing Xu; Jing Xu; JinRong Xu; Liang Xu; Wen Wen Xu; Xiulong Xu; Yu Xue; Sokhna M S Yakhine-Diop; Masamitsu Yamaguchi; Osamu Yamaguchi; Ai Yamamoto; Shunhei Yamashina; Shengmin Yan; Shian-Jang Yan; Zhen Yan; Yasuo Yanagi; Chuanbin Yang; Dun-Sheng Yang; Huan Yang; Huang-Tian Yang; Hui Yang; Jin-Ming Yang; Jing Yang; Jingyu Yang; Ling Yang; Liu Yang; Ming Yang; Pei-Ming Yang; Qian Yang; Seungwon Yang; Shu Yang; Shun-Fa Yang; Wannian Yang; Wei Yuan Yang; Xiaoyong Yang; Xuesong Yang; Yi Yang; Ying Yang; Honghong Yao; Shenggen Yao; Xiaoqiang Yao; Yong-Gang Yao; Yong-Ming Yao; Takahiro Yasui; Meysam Yazdankhah; Paul M Yen; Cong Yi; Xiao-Ming Yin; Yanhai Yin; Zhangyuan Yin; Ziyi Yin; Meidan Ying; Zheng Ying; Calvin K Yip; Stephanie Pei Tung Yiu; Young H Yoo; Kiyotsugu Yoshida; Saori R Yoshii; Tamotsu Yoshimori; Bahman Yousefi; Boxuan Yu; Haiyang Yu; Jun Yu; Jun Yu; Li Yu; Ming-Lung Yu; Seong-Woon Yu; Victor C Yu; W Haung Yu; Zhengping Yu; Zhou Yu; Junying Yuan; Ling-Qing Yuan; Shilin Yuan; Shyng-Shiou F Yuan; Yanggang Yuan; Zengqiang Yuan; Jianbo Yue; Zhenyu Yue; Jeanho Yun; Raymond L Yung; David N Zacks; Gabriele Zaffagnini; Vanessa O Zambelli; Isabella Zanella; Qun S Zang; Sara Zanivan; Silvia Zappavigna; Pilar Zaragoza; Konstantinos S Zarbalis; Amir Zarebkohan; Amira Zarrouk; Scott O Zeitlin; Jialiu Zeng; Ju-Deng Zeng; Eva Žerovnik; Lixuan Zhan; Bin Zhang; Donna D Zhang; Hanlin Zhang; Hong Zhang; Hong Zhang; Honghe Zhang; Huafeng Zhang; Huaye Zhang; Hui Zhang; Hui-Ling Zhang; Jianbin Zhang; Jianhua Zhang; Jing-Pu Zhang; Kalin Y B Zhang; Leshuai W Zhang; Lin Zhang; Lisheng Zhang; Lu Zhang; Luoying Zhang; Menghuan Zhang; Peng Zhang; Sheng Zhang; Wei Zhang; Xiangnan Zhang; Xiao-Wei Zhang; Xiaolei Zhang; Xiaoyan Zhang; Xin Zhang; Xinxin Zhang; Xu Dong Zhang; Yang Zhang; Yanjin Zhang; Yi Zhang; Ying-Dong Zhang; Yingmei Zhang; Yuan-Yuan Zhang; Yuchen Zhang; Zhe Zhang; Zhengguang Zhang; Zhibing Zhang; Zhihai Zhang; Zhiyong Zhang; Zili Zhang; Haobin Zhao; Lei Zhao; Shuang Zhao; Tongbiao Zhao; Xiao-Fan Zhao; Ying Zhao; Yongchao Zhao; Yongliang Zhao; Yuting Zhao; Guoping Zheng; Kai Zheng; Ling Zheng; Shizhong Zheng; Xi-Long Zheng; Yi Zheng; Zu-Guo Zheng; Boris Zhivotovsky; Qing Zhong; Ao Zhou; Ben Zhou; Cefan Zhou; Gang Zhou; Hao Zhou; Hong Zhou; Hongbo Zhou; Jie Zhou; Jing Zhou; Jing Zhou; Jiyong Zhou; Kailiang Zhou; Rongjia Zhou; Xu-Jie Zhou; Yanshuang Zhou; Yinghong Zhou; Yubin Zhou; Zheng-Yu Zhou; Zhou Zhou; Binglin Zhu; Changlian Zhu; Guo-Qing Zhu; Haining Zhu; Hongxin Zhu; Hua Zhu; Wei-Guo Zhu; Yanping Zhu; Yushan Zhu; Haixia Zhuang; Xiaohong Zhuang; Katarzyna Zientara-Rytter; Christine M Zimmermann; Elena Ziviani; Teresa Zoladek; Wei-Xing Zong; Dmitry B Zorov; Antonio Zorzano; Weiping Zou; Zhen Zou; Zhengzhi Zou; Steven Zuryn; Werner Zwerschke; Beate Brand-Saberi; X Charlie Dong; Chandra Shekar Kenchappa; Zuguo Li; Yong Lin; Shigeru Oshima; Yueguang Rong; Judith C Sluimer; Christina L Stallings; Chun-Kit Tong Journal: Autophagy Date: 2021-02-08 Impact factor: 13.391
Authors: Matteo Rossi; David Colecchia; Gennaro Ilardi; Mario Acunzo; Giovanni Nigita; Federica Sasdelli; Angela Celetti; Angela Strambi; Stefania Staibano; Carlo Maria Croce; Mario Chiariello Journal: Oncotarget Date: 2016-04-12
Authors: Q Heydt; C Larrue; E Saland; S Bertoli; J-E Sarry; A Besson; S Manenti; C Joffre; V Mansat-De Mas Journal: Oncogene Date: 2017-10-23 Impact factor: 9.867
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.
Figure 9.