RELATIONSHIP BETWEEN P21 EXPRESSION AND MUTATION OF THE P53 TUMOR-SUPPRESSOR GENE IN NORMAL AND MALIGNANT OVARIAN EPITHELIAL-CELLS

In many cell types, p53-mediated growth inhibition is dependent on ind uction of p21, which is an inhibitor of cyclin-dependent kinases that are required for cell cycle progression, Failure of mutant p53 protein s to transactivate p21 may lead to uncontrolled proliferation, Because many ovarian cancers have mutations in the p53 gene, me examined p21 levels in normal and malignant ovarian epithelial cells to determine w hether p21 expression is dependent on wild-type p53. Normal ovarian ep ithelial cells and two ovarian cancer cell lines with wild-type p53 ex pressed readily detectable levels of p21, whereas in p53 null and muta nt cell lines, expression of p21 was diminished strikingly, A correlat ion between the status of the p53 gene and p21 expression also was not ed in 23 primary epithelial ovarian cancers, Normal levels of p21 RNA were seen in 4/7 (57%) cancers with wild-type p53, whereas 14/16 (88%) cancers with mutant p53 had reduced p21 expression (P < 0.05), In add ition, we found that gamma-irradiation of normal and malignant ovarian epithelial cells with wild-type, but not mutant, p53 resulted in indu ction of p21, These data are suggestive that induction of p21 is a fea ture of p53-mediated growth inhibition in normal ovarian epithelial ce lls, Conversely, mutation of the p53 gene in ovarian cancers usually i s associated with decreased p21 expression, The lack of an absolute co rrelation between p21 expression and the status of the p53 gene in ova rian cancers is consistent with other studies that have suggested that p21 may also be regulated by p53-independent pathways.