title: Skp2 is required for incretin hormone-mediated β-cell proliferation.
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.
authors: Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095-7073, USA.
authors: Shuen-Ing
authors: SI
authors: Tschen
authors: Senta
authors: S
authors: Georgia
authors: Sangeeta
authors: S
authors: Dhawan
authors: Anil
authors: A
authors: Bhushan
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D000077270:Exenatide; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D054795:Incretins / Q000494:pharmacology / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology
chemical_list: C526297:IRS2 protein, human; D054795:Incretins; D055504:Insulin Receptor Substrate Proteins; D010455:Peptides; D044786:S-Phase Kinase-Associated Proteins; D014688:Venoms; D050760:Cyclin-Dependent Kinase Inhibitor p27; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D019869:Phosphatidylinositol 3-Kinases