Rapamycin inhibits growth factor-induced cell cycle regulation in pancreatic β cells

Amy Aronovitz, Jami Josefson, Amanda Fisher, Marsha Newman, Elizabeth Hughes, Fei Chen, David S. Moons, Hiroaki Kiyokawa, William L. Lowe

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

A progressive decline in islet function is a major obstacle to the success of islet transplantation. The cause of this decline in islet function is unclear, but immunosuppressive agents may contribute. Insulin-like growth factor-I (IGF-I) and betacellulin are important for islet cell survival and/or proliferation. In the present study, we performed studies in INS-1 cells and murine islets to define the effect of IGF-I and betacellulin on progression of islet cells through the cell cycle and the impact of immunosuppressive agents. Treatment of INS-1 cells for 24 hours with 20 ng/mL betacellulin or 50 ng/mL IGF-I increased cells in S phase by ∼2-fold. Treatment of INS-1 cells with IGF-I or betacellulin also increased cyclin D1 expression and nuclear exclusion of the cyclin-dependent kinase inhibitors p21Cip1 and p27 Kip1. In INS-1 cells and islets, betacellulin- and IGF-I increased Akt, extracellular signal-related kinase, and p70S6 kinase phosphorylation. Rapamycin, an immunosuppressant which inhibits mammalian target of rapamycin, inhibited the increase in p70S6 kinase phosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I-induced entry of cells into S phase and 5′-Bromo-2′-deoxyuridine incorporation as well as the effect of betacellulin and IGF-I on cyclin D1 expression and nuclear exclusion of p21 Cip1 and p27Kip1. Together, these data suggest that the effect of betacellulin and IGF-I on islet cell growth and proliferation is mediated, in part, via signaling through mammalian target of rapamycin. As rapamycin is used to treat islet transplant recipients, these results suggest that rapa-mycin could have deleterious effects on islet proliferation and function over time.

Original languageEnglish (US)
Pages (from-to)985-996
Number of pages12
JournalJournal of Investigative Medicine
Volume56
Issue number8
DOIs
StatePublished - Dec 2008

Keywords

  • Betacellulin
  • Insulin-like growth factor-I
  • Islet
  • Rapamycin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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