Rapamycin inhibits growth factor-induced cell cycle regulation in pancreatic beta cells.
A progressive decline in islet function is a major obstacle to success of islet transplantation. The cause of this decline is 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 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-1 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 cyclindependent kinase inhibitors p21(Cip1) and p27(Kip1). In INS-1 cells and islets, betacellulin- and IGF-I increased the increase in p70(s6 kinase) phosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I IN IGF-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 p(27Kip1). 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.
Aronovitz
Amy
A
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, chicago, IL 60611, USA.
Josefson
Jami
J
Fisher
Amanda
A
Newman
Marsha
M
Hughes
Elizabeth
E
Chen
Fei
F
Moons
David S
DS
Kiyokawa
Hiroaki
H
Lowe
William L
WL
D000818:Animals; D066259:Betacellulin; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*
D066259:Betacellulin; C587852:Btc protein, mouse; C587853:Btc protein, rat; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D036341:Intercellular Signaling Peptides and Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I; D020123:Sirolimus