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Rapamycin Inhibits Growth Factor-Induced Cell Cycle Regulation in Pancreatic β Cells
  1. Amy Aronovitz, MD,
  2. Jami Josefson, MD,
  3. Amanda Fisher, BS,
  4. Marsha Newman, MS,
  5. Elizabeth Hughes, MS,
  6. Fei Chen, BS,
  7. David S. Moons, MD, PhD,
  8. Hiroaki Kiyokawa, MD, PhD,
  9. William L. Lowe Jr, MD
  1. From the *Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Med; †Department of Pediatrics, Children's Memorial Hospital and Northwestern University Feinberg School of Medicine; ‡Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine; and §Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL.
  1. Supported by RO1 HD38085 and RO1 EB003806 from the National Institutes of Health, PPG # 4-2004-781 from the Juvenile Diabetes Research Foundation, the Searle Leadership Fund, and the Zell Scholar Fund as well as the Butz Foundation and Northwestern Memorial Foundation.
  2. Amy Aronovitz and Jami Josefson contributed equally to this work.
  3. Figures 5 and 6 can be viewed online in color at http://www.jinvestigativemed.com.
  4. Reprints: William L. Lowe, Jr, MD, Center for Endocrinology, Metabolism, and Molecular Medicine, Tarry 15-703, Northwestern University Feinberg School of Medicine, 303 East Chicago Ave., Chicago, IL 60611. E-mail: wlowe{at}northwestern.edu.

Abstract

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 p27Kip1. 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 p21Cip1 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 rapamycin could have deleterious effects on islet proliferation and function over time.

Key Words
  • betacellulin
  • insulin-like growth factor-I
  • islet
  • rapamycin

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