CONTEXT: Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden syndrome (CS) and Cowden-like syndrome (CSL) that predisposes to high risks of benign and malignant tumors of thyroid and breast. OBJECTIVE: The objective of the study was to analyze the subcellular pattern of phosphorylated (P)-AKT expression in nonmedullary thyroid cancers from PTEN hamartoma tumor syndrome patients and to investigate whether the lack of PTEN in the nucleus and/or lack of proper PTEN function in the nucleus affect(s) nuclear AKT activity in CS patients. DESIGN: In all, 664 patients with CS/CSL were screened for PTEN germline mutations and nonmedullary thyroid cancers. Twenty-two patients who have both pathogenic PTEN germline mutations and nonmedullary thyroid cancers were selected. Thyroid samples from these patients were stained for PTEN and P-AKT. In our in vitro study, PTEN was knocked down or overexpressed in both thyroid cancer cells and breast cancer cells, and nuclear P-AKT was compared with the control. RESULTS: Loss of PTEN protein was found in thyroid adenomas and carcinomas from all 22 (100%) PTEN(Mut+) CS/CSL patients. AKT activation was identified in 17 of 22 (77.3%) thyroid adenoma/carcinoma specimens, and most patients (63.7%) have activated nuclear AKT. Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase-dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells. We also showed that in breast cancer but not thyroid cancer cells, PTEN suppresses nuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3/P-AKT reservoir in the cytoplasm. In thyroid cancer cells, PTEN suppresses phosphorylation of AKT already resident in the nucleus. CONCLUSIONS: PTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.
CONTEXT: Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden syndrome (CS) and Cowden-like syndrome (CSL) that predisposes to high risks of benign and malignant tumors of thyroid and breast. OBJECTIVE: The objective of the study was to analyze the subcellular pattern of phosphorylated (P)-AKT expression in nonmedullary thyroid cancers from PTEN hamartoma tumor syndromepatients and to investigate whether the lack of PTEN in the nucleus and/or lack of proper PTEN function in the nucleus affect(s) nuclear AKT activity in CS patients. DESIGN: In all, 664 patients with CS/CSL were screened for PTEN germline mutations and nonmedullary thyroid cancers. Twenty-two patients who have both pathogenic PTEN germline mutations and nonmedullary thyroid cancers were selected. Thyroid samples from these patients were stained for PTEN and P-AKT. In our in vitro study, PTEN was knocked down or overexpressed in both thyroid cancer cells and breast cancer cells, and nuclear P-AKT was compared with the control. RESULTS: Loss of PTEN protein was found in thyroid adenomas and carcinomas from all 22 (100%) PTEN(Mut+) CS/CSLpatients. AKT activation was identified in 17 of 22 (77.3%) thyroid adenoma/carcinoma specimens, and most patients (63.7%) have activated nuclear AKT. Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase-dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells. We also showed that in breast cancer but not thyroid cancer cells, PTEN suppresses nuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3/P-AKT reservoir in the cytoplasm. In thyroid cancer cells, PTEN suppresses phosphorylation of AKT already resident in the nucleus. CONCLUSIONS:PTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.
Authors: K Tanaka; K Horiguchi; T Yoshida; M Takeda; H Fujisawa; K Takeuchi; M Umeda; S Kato; S Ihara; S Nagata; Y Fukui Journal: J Biol Chem Date: 1999-02-12 Impact factor: 5.157
Authors: D Liaw; D J Marsh; J Li; P L Dahia; S I Wang; Z Zheng; S Bose; K M Call; H C Tsou; M Peacocke; C Eng; R Parsons Journal: Nat Genet Date: 1997-05 Impact factor: 38.330
Authors: Juinn-Lin Liu; Xiaoyang Sheng; Zsuzsanna K Hortobagyi; Zhenyu Mao; Gary E Gallick; W K Alfred Yung Journal: Mol Cell Biol Date: 2005-07 Impact factor: 4.272
Authors: A Perren; L P Weng; A H Boag; U Ziebold; K Thakore; P L Dahia; P Komminoth; J A Lees; L M Mulligan; G L Mutter; C Eng Journal: Am J Pathol Date: 1999-10 Impact factor: 4.307
Authors: V Vasko; M Saji; E Hardy; M Kruhlak; A Larin; V Savchenko; M Miyakawa; O Isozaki; H Murakami; T Tsushima; K D Burman; C De Micco; M D Ringel Journal: J Med Genet Date: 2004-03 Impact factor: 6.318
Authors: H E Feilotter; V Coulon; J L McVeigh; A H Boag; F Dorion-Bonnet; B Duboué; W C Latham; C Eng; L M Mulligan; M Longy Journal: Br J Cancer Date: 1999-02 Impact factor: 7.640