Stromal cell-derived factor-1 promotes survival of pancreatic beta cells by the stabilisation of beta-catenin and activation of transcription factor 7-like 2 (TCF7L2).
OBJECTIVE
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
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.
Liu
Z
Z
Thier 306, Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Habener
J F
JF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D017930:Genes, Reporter; D018257:Helix-Loop-Helix Motifs; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D051820:TCF Transcription Factors / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*; D001616:beta-Galactosidase / Q000235:genetics
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D019284:Thapsigargin; D001616:beta-Galactosidase