GROWTH ARREST BY THE CYCLIN-DEPENDENT KINASE INHIBITOR P27(KIP1) IS ABROGATED BY C-MYC

We show here that c-Myc antagonizes the cyclin-dependent kinase (CDK) inhibitor p27(Kip1). p27 expressed from recombinant retroviruses in Ra t1 cells associated with and inhibited cyclin E/CDK2 complexes, induce d accumulation of the pRb and p130 proteins in their hypophosphorylate d forms, and arrested cells in G(1). Prior expression of c-Myc prevent ed inactivation of cyclin E/CDK2 as well as dephosphorylation of pRb a nd p130, and allowed continuous cell proliferation in the presence of p27, This effect did not require ubiquitin-mediated degradation of p27 . Myc altered neither the susceptibility of cyclin E/CDK2 to inhibitio n by p27, nor the intrinsic CDK-inhibitory activity of p27, but induce d sequestration of p27 in a form unable to bind cyclin E/CDK2, Neither Myc itself nor other G(1)-cyclin/CDK complexes were directly responsi ble for p27 sequestration, Retroviral expression of G(1) cyclins (D1-3 , E or A) or of the Cdc25A phosphatase did not overcome p27-induced ar rest, Growth rescue by Myc required dimerization with Max, DNA binding and an intact transcriptional activation domain, as previously shown for cellular transformation, We propose that this activity is mediated by the product of an as yet unknown Myc-Max target gene(s) and repres ents an essential aspect of Myc's mitogenic and oncogenic functions.