Work

Skp2 Is Required for Incretin Hormone-Mediated β-Cell Proliferation

Year: 2011

Type: article

Abstract: The glucoincretin hormone glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (Ex-4) promote β-cell growth and expansion. Here we report an essential role for Skp2, a substrate recognition component of SCF (Skp, Cullin, F-box) ubiquitin ligase, in promoting glucoincretin-induced β-cell proliferation by regulating the cellular abundance of p27. In vitro, GLP-1 treatment increases Skp2 levels, which accelerates p27 degradation, whereas in vivo, loss of Skp2 prevents glucoincretin-induced β-cell proliferation. Using inhibitors of phosphatidylinositol 3-kinase and Irs2 silencing RNA, we also show that the effects of GLP-1 in facilitating Skp2-dependent p27 degradation are mediated via the Irs2-phosphatidylinositol-3 kinase pathway. Finally, we show that down-regulation of p27 occurs in islets from aged mice and humans, although in these islets, age-dependent accumulation of p16(Ink4a) prevent glucoincretin-induced β-cell proliferation; however, ductal cell proliferation is maintained. Taken together, these data highlight a critical role for Skp2 in glucoincretin-induced β-cell proliferation.

Source: Molecular Endocrinology

DOI: 10.1210/me.2011-1119

Authors: Shuen-Ing Tschen, Senta Georgia, Sangeeta Dhawan, Anil Bhushan

Institution: University of California, Los Angeles

Language: English

Topic: Pancreatic function and diabetes

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Leona M. and Harry B. Helmsley Charitable Trust, National Institutes of Health, University of California, Los Angeles, National Institute of Diabetes and Digestive and Kidney Diseases