INTERFERENCE WITH P53 PROTEIN INHIBITS HEMATOPOIETIC AND MUSCLE DIFFERENTIATION

The involvement of p53 protein in cell differentiation has been recent ly suggested by some observations made with tumor cells and the correl ation found between differentiation and increased levels of p53. Howev er, the effect of p53 on differentiation is in apparent contrast with the normal development of p53-null mice. To test directly whether p53 has a function in cell differentiation, we interfered with the endogen ous wt-p53 protein of nontransformed cells of two different murine his totypes: 32D myeloid progenitors, and C2C12 myoblasts. A drastic inhib ition of terminal differentiation into granulocytes or myotubes, respe ctively, was observed upon expression of dominant-negative p53 protein s. This inhibition did not alter the cell cycle withdrawal typical of terminal differentiation, nor p21((WAF1/CIP1)) upregulation, indicatin g that interference with endogenous p53 directly affects cell differen tiation, independently of the p53 activity on the cell cycle. We also found that the endogenous wt-p53 protein of C2C12 cells becomes transc riptionally active during myogenesis, and this activity is inhibited b y p53 dominant-negative expression. Moreover, we found that p53 DNA-bi nding and transcriptional activities are both required to induce diffe rentiation in p53-negative K562 cells. Taken together, these data stro ngly indicate that p53 is a regulator of cell differentiation and it e xerts this role, at least in part, through its transcriptional activit y.