ENDOGENOUS P53 REGULATION AND FUNCTION IN EARLY-STAGE FRIEND VIRUS-INDUCED TUMOR PROGRESSION DIFFERS FROM THAT FOLLOWING DNA-DAMAGE

Erythroleukemia induced by the anemia strain of Friend virus occurs in two stages, The first stage results in rapid expansion of pre-leukemi c proerythroblasts (FVA cells) dependent on erythropoietin (Epo) for d ifferentiation and survival in vitro. The second stage is characterize d by emergence of erythroleukemic clones (MEL cells) which typically b ear activation of the ets-oncogene, PU.1/spi.1, and loss of functional p53. We developed a Friend virus-sensitive, p53-deficient mouse model to investigate the biological advantage conferred by p53-loss during tumor progression. Here we report p53 was not required for cell surviv al or growth arrest during differentiation of FVA cells, nor was p53 r equired for induction of apoptosis upon Epo withdrawal. However, we de tected induction of the p21(Cip1) cyclin-dependent kinase inhibitor ge ne during differentiation, which was markedly enhanced in the presence of p53. p53-dependent expression of p21(Cip1) occurred in the absence of an increase in p53 mRNA and protein levels and was specific for p2 1(Cip1) since expression of gadd45, mdm-2, cyclin G and bax were unaff ected by p53. In contrast, treatment of FVA cells with DNA damaging ag ents led to rapid accumulation of p53 protein resulting in transcripti on of multiple p53-regulated genes, leading to either apoptosis or gro wth arrest, depending on the agent used. These data demonstrate that p 53-dependent activities during differentiation of preleukemic erythrob lasts are distinct from those observed in response to genotoxic agents . We propose that enhancement of p53-dependent gene expression during differentiation may represent a tumor suppressor function which is nec essary to monitor differentiation of preleukemic cells and which is se lected against during tumor progression.