title: Wnt3a regulates proliferation, apoptosis and function of pancreatic NIT-1 beta cells via activation of IRS2/PI3K signaling.
abstract: Wnt-signaling pathway is implicated in pancreatic development and functional regulation of mature beta-cells. Wnt3a/Wnt pathway activation expands islet cell mass in vitro by increasing proliferation and decreasing apoptosis of beta-cells, thereby enhancing its function. However, the signaling pathways that mediate these effects remain unknown. By using a clonal beta-cell line (NIT-1), we examined the role of IRS2/PI3K in the mediation of Wnt3a-stimulated beta-cell growth. Real-time PCR and Western blot were employed to investigate the activity of Wnt/β-catenin and IRS2/PI3K signaling. Proliferation of NIT-1 cells was assessed by BrdU incorporation, and apoptosis was quantitatively determined by TUNEL and flow cytometry (FCM). Dkk1, an inhibitor of Wnt signaling, and wortmannin, an inhibitor of PI3K, were also used. Results showed that Wnt3a rapidly activated Wnt/β-catenin signaling, promoted IRS2 expression and Akt phosphorylation in NIT-1 cells. These effects were completely abrogated by Dkk1 or partially eliminated by wortmannin. Wnt3a also promoted NIT-1 cell proliferation, inhibited cytokine-induced beta-cell apoptosis, and increased insulin secretion. Both of these effects were also eliminated by Dkk1 or wortmannin. Our results demonstrated that Wnt3a regulates proliferation, apoptosis and enhances function of pancreatic NIT-1 beta cells via activation of Wnt/β-catenin signaling, involving crosstalk with IRS2/PI3K signaling, with the effect of Wnt signaling on beta-cells also being IRS2/PI3K/AKT dependent.
authors.affiliation: Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Gui
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Xue
authors.forename: Yikai
authors.initials: Y
authors.lastname: Yu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Muxun
authors.initials: M
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D005434:Flow Cytometry; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D060509:Wnt3A Protein; D019869:Phosphatidylinositol 3-Kinases