Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells.
Differentiating 3T3-L1 cells express an immunophilin early during the adipocyte conversion program as described in this issue [Yeh, W.-C., Li, T.-K., Bierer, B. E. & McKnight, S. L. (1995) Proc. Natl. Acad. Sci. USA 92, 11081-11085]. The temporal expression profile of this protein, designated FK506-binding protein (FKBP) 51, is concordant with the clonal-expansion period undertaken by 3T3-L1 cells after exposure to adipogenic hormones. Having observed FKBP51 synthesis early during adipogenesis, we tested the effects of three immunosuppressive drugs--cyclosporin A, FK506, and rapamycin--on the terminal-differentiation process. Adipocyte conversion was not affected by either cyclosporin A or FK506 and yet was significantly reduced by rapamycin at drug concentrations as low as 10 nM. Clonal expansion was impeded in drug-treated cultures, as was the accumulation of cytoplasmic lipid droplets normally seen late during differentiation. Rapamycin treatment likewise inhibited the expression of CCAAT/enhancer binding protein alpha, a transcription factor required for 3T3-L1 cell differentiation. All three of these effects were reversed by high FK506 concentrations, indicating that the operative inhibitory event was mediated by an immunophilin-rapamycin complex.
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D002999:Clone Cells / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011090:Polyenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D009687:Nuclear Proteins; D011090:Polyenes; D012333:RNA, Messenger; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus