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Mol Endocrinol. 2011 Dec;25(12):2134-43. doi: 10.1210/me.2011-1119. Epub 2011 Oct 6.

Skp2 is required for incretin hormone-mediated β-cell proliferation.

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1
Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095-7073, USA.

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.

PMID:
21980072
PMCID:
PMC3231831
DOI:
10.1210/me.2011-1119
[Indexed for MEDLINE]
Free PMC Article
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