MUTANT P53 RESCUES HUMAN-DIPLOID CELLS FROM SENESCENCE WITHOUT INHIBITING THE INDUCTION OF SDI1 WAF1/

Although the cyclin-dependent kinase inhibitor p21(SD11) (WAF1/CIP1) h as been proposed as the mediator of p53-induced cell cycle arrest foll owing DNA damage, several stimuli now appear to induce SDI1 independen t of p53 function. We have examined the behavior of p53 and SDI1 in an isogeneic model by manipulating p53 status in normal diploid human fi broblasts using an amphotropic retroviral vector. Following DNA strand break damage induced by bleomycin, both SDI1 induction and G(1)-S cel l cycle arrest are p53 dependent, consistent with SDI1 being the key m ediator. In contrast, in cellular senescence (and following UV irradia tion), induction of SDI1 occurs independent of p53 function yet growth arrest is still p53 dependent. We conclude (a) that redundant pathway s exist for induction of SDI1, but that (b) SDI1, while perhaps necess ary, is not sufficient for inhibition of cell cycle progression, requi ring the cooperation of an additional factor (possibly another cyclin- dependent kinase inhibitor) whose expression, at least in the case of senescence, is strictly p53 dependent.