Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line.
Rapamycin is a potent immunosuppressant that binds to the cytosolic protein, FKBP12, and blocks T cell activation. Here we report that rapamycin also blocks myogenic proliferation and induces differentiation, associated with a decrease in p34cdc2 activity and cyclin A levels. In yeast and mammals, rapamycin blocks cell cycle progression by causing G1 arrest, arguing for a conserved signaling pathway governing the G1 to S transition. p34cdc2 has been shown to play a role in both the transition from G1 to S and from G2 to M in yeast. In higher eukaryotes the role of p34cdc2 in G1 to S transition is less clear. Rapamycin and the structurally related macrolide antibiotic FK506 both bind to a cytosolic protein, the FK506-binding protein (FKBP12). We show that inhibition of myogenic proliferation is achieved at low doses of rapamycin (< 1 ng/ml) and is competed by a molar excess of FK506, indicating specificity for FKBP12. The distinct FK506-calcineurin pathway did not affect myogenic proliferation, differentiation, or p34cdc2 kinase activity. Thus, the rapamycin-FKBP12 signaling pathway involves a specific and direct effect on p34cdc2 kinase activity at the G1 to S transition and identifies a regulatory step during myogenic differentiation.
Jayaraman
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Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029.
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D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D009132:Muscles / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D011090:Polyenes / Q000378:metabolism / Q000494:pharmacology*; D020123:Sirolimus; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D016213:Cyclins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D016203:CDC2 Protein Kinase; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus