LOSS OF P21(CIP1 WAF1) DOES NOT RECAPITULATE ACCELERATED MALIGNANT CONVERSION CAUSED BY P53 LOSS IN EXPERIMENTAL SKIN CARCINOGENESIS/

The p21(CIP1/WAF1) protein is considered a downstream effector of tumo r suppression by p53, We have previously demonstrated that p53 null ke ratinocytes have lower basal p21(CIP1/WAF1) mRNA levels and that tumor s derived from these cells following transduction with the v-ras(Ha) o ncogene grow faster than wildtype keratinocytes and rapidly progress t o undifferentiated carcinomas (Cancer Res 54: 5584-5592, 1994), In thi s study, primary keratinocytes differing in p21(CIP1/WAF1) gene dose w ere transduced with v-ras(Ha) encoding retrovirus and grafted to nude mouse hosts to test whether the p53 null phenotype is mediated through p21(CIP1/WAF1). Resulting tumors from all genotypes were well differe ntiated papillomas; focal carcinomas were observed in 43, 30 and 44% o f papillomas derived from +/+, +/- and -/- keratinocytes, respectively , p21(CIP1/WAF1) deficient keratinocytes expressing v-ras(Ha) do not d isplay the degree of increased growth observed in p53 deficient tumors irt vivo or the decreased responsiveness to negative growth regulatio n by Ca2+ in vitro. These results suggest that p21(CIP1/WAF1) does not regulate the differentiated phenotype or malignant progression of v-r as(Ha) initiated keratinocytes and that additional functions of the p5 3 protein other than transcriptional regulation Of the p21(CIP1/WAF1) gene are required for p53 mediated tumor suppression.