Z Liu1, J F Habener. 1. Thier 306, Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Abstract
AIMS/HYPOTHESIS: Stromal cell-derived factor-1 (SDF-1) is a chemokine produced in stromal tissues in multiple organs. Earlier we reported on levels of SDF-1 and SDF-1 receptor (CXCR4) in the insulin-producing beta cells of the mouse pancreas and determined that the SDF-1/CXCR4 axis is important for beta cell survival through activation of the prosurvival kinase, protein kinase B (AKT). Since AKT is known to modulate the wingless-type MMTV integration site family (WNT) signalling cascade, we examined the effects of SDF-1/CXCR4 on WNT signalling in beta cells and whether this signalling is important for cell survival. METHODS: Activation of downstream WNT signalling (beta-catenin and transcription factor 7-like 2, [TCF7L2]) in response to SDF-1 was examined in the islets of WNT signalling reporter (Tcf-optimal promoter beta-galactosidase) mice and in INS-1 and MIN6 beta cells. Cytoprotection of beta cells by SDF-1 in response to the induction of apoptosis was assessed by caspase 3 and TUNEL assays. RESULTS: SDF-1 induced WNT signalling in beta cells of isolated islets and in INS-1 cells via CXCR4-mediated activation of Galphai/o-coupled signalling and the phosphatidylinositol 3-kinase/AKT signalling cascade resulting in the inhibition of glycogen synthase kinase 3-beta. The key WNT signalling regulators, beta-catenin and AKT, were activated by SDF-1 at the transcriptional and post-translational levels. Specific inhibition of beta-catenin in the WNT signalling cascade reversed the anti-apoptotic effects of SDF-1. CONCLUSIONS/ INTERPRETATION: SDF-1 promotes pancreatic beta cell survival via activation of AKT and downstream WNT signalling via the stabilisation and activation of beta-catenin/TCF7L2 transcriptional activators. These findings suggest a mechanism for SDF-1 based glucose-lowering therapies by enhancing beta cell mass through increasing cell survival.
AIMS/HYPOTHESIS: Stromal cell-derived factor-1 (SDF-1) is a chemokine produced in stromal tissues in multiple organs. Earlier we reported on levels of SDF-1 and SDF-1 receptor (CXCR4) in the insulin-producing beta cells of the mousepancreas and determined that the SDF-1/CXCR4 axis is important for beta cell survival through activation of the prosurvival kinase, protein kinase B (AKT). Since AKT is known to modulate the wingless-type MMTV integration site family (WNT) signalling cascade, we examined the effects of SDF-1/CXCR4 on WNT signalling in beta cells and whether this signalling is important for cell survival. METHODS: Activation of downstream WNT signalling (beta-catenin and transcription factor 7-like 2, [TCF7L2]) in response to SDF-1 was examined in the islets of WNT signalling reporter (Tcf-optimal promoter beta-galactosidase) mice and in INS-1 and MIN6 beta cells. Cytoprotection of beta cells by SDF-1 in response to the induction of apoptosis was assessed by caspase 3 and TUNEL assays. RESULTS:SDF-1 induced WNT signalling in beta cells of isolated islets and in INS-1 cells via CXCR4-mediated activation of Galphai/o-coupled signalling and the phosphatidylinositol 3-kinase/AKT signalling cascade resulting in the inhibition of glycogen synthase kinase 3-beta. The key WNT signalling regulators, beta-catenin and AKT, were activated by SDF-1 at the transcriptional and post-translational levels. Specific inhibition of beta-catenin in the WNT signalling cascade reversed the anti-apoptotic effects of SDF-1. CONCLUSIONS/ INTERPRETATION:SDF-1 promotes pancreatic beta cell survival via activation of AKT and downstream WNT signalling via the stabilisation and activation of beta-catenin/TCF7L2 transcriptional activators. These findings suggest a mechanism for SDF-1 based glucose-lowering therapies by enhancing beta cell mass through increasing cell survival.
Authors: Sheng-Bin Peng; Victoria Peek; Yan Zhai; Donald C Paul; Qinyuan Lou; Xiaoling Xia; Thomas Eessalu; Wayne Kohn; Shaoqing Tang Journal: Mol Cancer Res Date: 2005-04 Impact factor: 5.852
Authors: Yvonne Döring; Heidi Noels; Emiel P C van der Vorst; Carlos Neideck; Virginia Egea; Maik Drechsler; Manuela Mandl; Lukas Pawig; Yvonne Jansen; Katrin Schröder; Kiril Bidzhekov; Remco T A Megens; Wendy Theelen; Barbara M Klinkhammer; Peter Boor; Leon Schurgers; Rick van Gorp; Christian Ries; Pascal J H Kusters; Allard van der Wal; Tilman M Hackeng; Gabor Gäbel; Ralf P Brandes; Oliver Soehnlein; Esther Lutgens; Dietmar Vestweber; Daniel Teupser; Lesca M Holdt; Daniel J Rader; Danish Saleheen; Christian Weber Journal: Circulation Date: 2017-04-27 Impact factor: 29.690
Authors: D Mokhtari; A Al-Amin; K Turpaev; T Li; O Idevall-Hagren; J Li; A Wuttke; R G Fred; P Ravassard; R Scharfmann; A Tengholm; N Welsh Journal: Diabetologia Date: 2013-03-05 Impact factor: 10.122