Evaluation of β-cell replication in mice transgenic for hepatocyte growth factor and placental lactogen: Comprehensive characterization of the G1/S regulatory proteins reveals unique involvement of p21 cip

Irene Cozar-Castellano, Matthew Weinstock, Marcia Haught, Silvia Velázquez-Garcia, Darinka Sipula, Andrew F. Stewart

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

We hypothesized that combined transgenic overexpression of hepatocyte growth factor (HGF) and placental lactogen in islets would lead to even greater increases in β-cell mass and replication than either growth factor alone. This did not occur, suggesting that β-cell replication is saturable or subject to molecular restraint. We therefore performed the first comprehensive G1/S cell cycle survey in islets, cataloguing the broad range of kinases, cyclins, and kinase inhibitors that control the G1/S transition in islets from normal, HGF, placental lactogen, and doubly transgenic mice. Many of the G1/S checkpoint regulators (E2Fs; pRb; p107; p130; cyclins D1,2,3, A, and E; cdk-2; cdk-4; p15; p16; p18; p19; p21; p27; MDM2; p53; c-Myc; and Egr-1) are present in the murine islet. Most of these proteins were unaltered by overexpression of HGF or placental lactogen, either alone or in combination. In contrast, p21cip was uniquely, dramatically, and reproducibly upregulated in placental lactogen and HGF islets. p21cip was also present in, and upregulated in, proliferating human islets, localizing specifically in β-cells and translocating to the nucleus on mitogenic stimulation. Homozygous p21cip loss releases islets from growth inhibition, markedly enhancing proliferation in response to HGF and placental lactogen.

Original languageEnglish
Pages (from-to)70-77
Number of pages8
JournalDiabetes
Volume55
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

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