POSTTRANSCRIPTIONAL STABILIZATION UNDERLIES P53-INDEPENDENT INDUCTIONOF P21(WAF1 CIP1/SDI1) IN DIFFERENTIATING HUMAN LEUKEMIC-CELLS/

p21(WAF1/CIP1/SDI1) is a recently identified gene expressed in cells h arboring wild-type but not mutant p53 gene. It encodes a nuclear prote in of 21 kD which inhibits cyclin-dependent kinase activity. Constitut ive p21(WAF1/CIP1/SDI1) mRNA expression was detected in neoplastic cel ls from patients with various hematological malignancies as well as in normal bone marrow mononuclear cells and in myeloid and lymphoid cell lines independent of their p53 status. Induced differentiation of the p53-deficient promyelocytic HL-60 cells along the monocytic lineage b y phorbol ester or 1a,25 dihydroxyvitamin D-3 resulted in a marked inc rease of both p21(WAF1/CIP1/SDI1) mRNA and protein expression due to e nhanced mRNA stability. Differentiation towards the granulocytic linea ge by all-trans retinoic acid or dimethylsulfoxide failed to produce t his effect. p21(WAF1/CIP1/SDI1) is an immediate early gene since its u pregulation occurred independently of de novo protein synthesis. The i nduction of p21(WAF1/CIP1/SDI1) expression and its regulation in p53-d eficient differentiating leukemic cells support the idea of an additio nal, p53-independent role of p21(WAF1/CIP1/SDI1) in human hematopoiesi s.