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Diabetologia

Erschienen in:

01.08.2009 | Article

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)

verfasst von: Z. Liu, J. F. Habener

Erschienen in: Diabetologia | Ausgabe 8/2009

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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.

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Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedCrossRef

Yano T, Liu Z, Donovan J, Thomas MK, Habener JF (2007) Stromal cell derived factor-1 (SDF-1)/CXCL12 attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase AKT. Diabetes 56:2946–2957PubMedCrossRef

Burger JA, Kipps TJ (2006) CXCR4 a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 107:1761–1767PubMedCrossRef

Kucia M, Ratajczak J, Ratajczak MZ (2005) Bone marrow as a source of circulating CXCR4+ tissue-committed stem cells. Biol Cell 97:133–146PubMedCrossRef

Ratajczak MZ, Zuba-Surma E, Kucia M, Reca R, Wojakowski W, Ratajczak J (2006) The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia 20:1915–1924PubMedCrossRef

Kryczek I, Wei S, Keller E, Liu R, Zou W (2007) Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol 292:C987–C995PubMedCrossRef

Schober A, Karshovska E, Zernecke A, Weber C (2006) SDF-1alpha-mediated tissue repair by stem cells: a promising tool in cardiovascular medicine? Trends Cardiovasc Med 16:103–112PubMedCrossRef

Dalakas E, Newsome PN, Harrison DJ, Plevris JN (2005) Hematopoietic stem cell trafficking in liver injury. FASEB J 19:1225–1231PubMedCrossRef

Nagasawa T, Hirota S, Tachibana K et al (1996) Defects of B cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382:635–638PubMedCrossRef

10.

Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595–599PubMedCrossRef

11.

Welters HJ, Kulkarni RN (2008) WNT signalling: relevance to beta cell biology and diabetes. Trends Endocrinol Metab 19:349–355PubMedCrossRef

12.

Kayali AG, van Gunst K, Campbell IL et al (2003) The stromal cell-derived factor-1alpha/CXCR4 ligand–receptor axis is critical for progenitor survival and migration in the pancreas. J Cell Biol 163:859–869PubMedCrossRef

13.

Ide A, Kawasaki E, Abiru N et al (2003) Stromal-cell derived factor-1 chemokine gene variant is associated with type 1 diabetes age at onset in Japanese population. Hum Immunol 64:973–978PubMedCrossRef

14.

Dubois-Laforgue D, Hendel H, Caillat-Zucman S et al (2001) A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes. Diabetes 50:1211–1213PubMedCrossRef

15.

Aboumrad E, Madec AM, Thivolet C (2007) The CXCR4/CXCL12 (SDF-1) signalling pathway protects non-obese diabetic mouse from autoimmune diabetes. Clin Exp Immunol 148:432–439PubMed

16.

Moon RT, Kohn AD, de Ferrari GV, Kaykas A (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5:691–701PubMedCrossRef

17.

Moon RT (2005) WNT/beta-catenin pathway. Sci STKE 2005:cm1

18.

Tian Q, Jin H, Cui Y, Guo C, Lu X (2005) Regulation of WNT gene expression. Dev Growth Differ 47:273–281PubMedCrossRef

19.

Nelson WJ, Nusse R (2004) Convergence of WNT, beta-catenin, and cadherin pathways. Science 303:1483–1487PubMedCrossRef

20.

Logan CY, Nusse R (2004) The WNT signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810PubMedCrossRef

21.

Gordon MD, Nusse R (2006) WNT signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 281:22429–22433PubMedCrossRef

22.

Liu Z, Habener JF (2008) Glucagon-like peptide-1 activation of TCF7L2-dependent WNT signaling enhances pancreatic beta cell proliferation. J Biol Chem 283:8723–8735PubMedCrossRef

23.

Florez JC (2008) Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51:1100–1110PubMedCrossRef

24.

Luo Y, Cai J, Xue H, Mattson MP, Rao MS (2006) SDF1alpha/CXCR4 signaling stimulates beta-catenin transcriptional activity in rat neural progenitors. Neurosci Lett 398:291–295PubMedCrossRef

25.

Lacy PE (1994) Pancreatic islet cell transplant. Mt Sinai J Med 61:23–31PubMed

26.

DasGupta R, Fuchs E (1999) Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126:4557–4568PubMed

27.

Peng SB, Peek V, Zhai Y et al (2005) AKT activation, but not extracellular signal-regulated kinase activation, is required for SDF-1alpha/CXCR4-mediated migration of epitheloid carcinoma cells. Mol Cancer Res 3:227–236PubMed

28.

Song WJ, Schreiber WE, Zhong E et al (2008) Exendin-4 stimulation of cyclin A2 in beta-cell proliferation. Diabetes 57:2371–2381PubMedCrossRef

29.

Jia L, Miao C, Cao Y, Duan EK (2008) Effects of WNT proteins on cell proliferation and apoptosis in HEK293 cells. Cell Biol Int 32:807–813PubMedCrossRef

30.

Wieczorek M, Paczkowska A, Guzenda P, Majorek M, Bednarek AK, Lamparska-Przybysz M (2008) Silencing of WNT-1 by siRNA induces apoptosis of MCF-7 human breast cancer cells. Cancer Biol Ther 7:268–274PubMed

31.

Wang X, Xiao Y, Mou Y, Zhao Y, Blankesteijn WM, Hall JL (2002) A role for the beta-catenin/T cell factor signaling cascade in vascular remodeling. Circ Res 90:340–347PubMedCrossRef

32.

Papadopoulou S, Edlund H (2005) Attenuated WNT signaling perturbs pancreatic growth but not pancreatic function. Diabetes 54:2844–2851PubMedCrossRef

33.

Ikonomou L, Geras-Raaka E, Raaka BM, Gershengorn MC (2008) Beta-catenin signaling in mesenchymal islet-derived precursor cells. Cell Prolif 41:474–491PubMedCrossRef

34.

Tian Q, Feetham MC, Tao WA et al (2004) Proteomic analysis identifies that 14-3-3zeta interacts with beta-catenin and facilitates its activation by AKT. Proc Natl Acad Sci U S A 101:15370–15375PubMedCrossRef

35.

Fang D, Hawke D, Zheng Y et al (2007) Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282:11221–11229PubMedCrossRef

Titel: 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)
verfasst von: Z. Liu
J. F. Habener
Publikationsdatum: 01.08.2009
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 8/2009
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-009-1384-x

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Methods

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