P53 FACILITATES PRB CLEAVAGE IN IL-3-DEPRIVED CELLS - NOVEL PRO-APOPTOTIC ACTIVITY OF P53

In the interleukin-3 (IL-3)-dependent lymphoid cell line DA-1, functio nal p53 is required for efficient apoptosis in response to IL-3 withdr awal. Activation of p53 in these cells, by either DNA damage or p53 ov erexpression, results in a vital growth arrest in the presence of IL-3 and in accelerated apoptosis in its absence. Thus, IL-3 can control t he choice between p53-dependent cell-cycle arrest and apoptosis, Here we report that the cross-talk between p53 and IL-3 involves joint cont rol of pRb cleavage and degradation. Depletion of IL-3 results in casp ase-mediated pRb cleavage, occurring preferentially within cells which express functional p53, Moreover, pRb can be cleaved efficiently by e xtracts prepared from DA-1 cells but not from their derivatives which lack p53 function. Inactivation of pRb through expression of the human papillomavirus (HPV) E7 oncogene overrides the effect of IL-3 in a p5 3-dependent manner. Our data suggest a novel role for p53 in the regul ation of cell death and a novel mechanism for the cooperation between p53 and survival factor deprivation. Thus, p53 makes cells permissive to pRb cleavage, probably by controlling the potential activity of a p Rb-cleaving caspase, whereas IL-3 withdrawal provides signals that tur n on this potential activity and lead to the actual cleavage and subse quent degradation of pRb, Elimination of a presumptive anti-apoptotic effect of pRb may then facilitate conversion of p53-mediated growth ar rest into apoptosis.