p27(kip1)-independent cell cycle regulation by MYC

MYC transcription factors are potent stimulators of cell proliferation. It has been suggested that the CDK-inhibitor p27(kip1) is a critical G1 phase cell cycle target of c-MYC. We show here that mouse embryo fibroblasts defi cient for both p27(kip1) and the related p21(cip1) are still responsive to stimulation by c-MYC and can be arrested in G1 by a dominant negative mutan t of c-MYC. This growth arrest can be overruled by ectopic expression of E2 F or adenovirus E1A, but not by a mutant of E1A defective for binding to re tinoblastoma family proteins. We show that fibroblasts with a genetic disru ption of all three retinoblastoma family members (pRb, p107 and p130) are u nresponsive to a dominant negative c-MYC mutant. These data indicate that p 27(kip1) is not the only rate limiting cell cycle target of c-MYC and sugge st that regulation of E2F is also essential for c-MYC's mitogenic activity.