ABROGATION OF P53-INDUCED CELL-CYCLE ARREST BY C-MYC - EVIDENCE FOR AN INHIBITOR OF P21(WAF1 CIP1/SDI1)/

The tumour-suppressor p53 inhibits cell cycle progression by direct tr ansactivation of the p21(WAF1/CIP1/SD11) gene, which encodes a univers al inhibitor of cyclin dependent kinases (cdk). The proto-oncogene pro duct c-Myc induces cell cycle progression and, in the absence of survi val factors, apoptosis. However, a direct link between the cell cycle machinery and c-Myc has not yet been established, We show that c-Myc a brogates a p53-induced G1-arrest without elevating the expression of c dks or cyclins involved in the G1/S-transition, Instead, the results s uggest that c-Myc interferes with the inhibitory action of p21 on cdk/ cyclin-complexes by inducing a heat-labile inhibitor of p21, The inact ivation of p21 and related cdk-inhibitors may explain several of the o ncogenic actions of c-Myc, including the induction of proliferation, i mmortalisation and the inhibition of differentiation. Modulation of cd k activity by the induction of an inhibitor of cdk-inhibitors represen ts a novel mechanism of cell cycle regulation in mammalian cells.