Loss of p21CIP1/WAF1 does not recapitulate accelerated malignant conversion caused by p53 loss in experimental skin carcinogenesis

The p21CIP1/WAF1 protein is considered a downstream effector of tumor suppression by p53. We have previously demonstrated that p53 null keratinocytes have lower basal p21CIP1/WAF1 mRNA levels and that tumors derived from these cells following transduction with the v-rasHa oncogene grow faster than wildtype keratinocytes and rapidly progress to undifferentiated carcinomas (Cancer Res 54: 5584 – 5592, 1994). In this study, primary keratinocytes differing in p21CIP1/WAF1 gene dose were transduced with v-rasHa encoding retrovirus and grafted to nude mouse hosts to test whether the p53 null phenotype is mediated through p21CIP1/WAF1. Resulting tumors from all genotypes were well differentiated papillomas; focal carcinomas were observed in 43, 30 and 44% of papillomas derived from +/+, +/− and −/− keratinocytes, respectively. p21CIP1/WAF1 deficient keratinocytes expressing v-rasHa do not display the degree of increased growth observed in p53 deficient tumors in vivo or the decreased responsiveness to negative growth regulation by Ca2+in vitro. These results suggest that p21CIP1/WAF1 does not regulate the differentiated phenotype or malignant progression of v-rasHa initiated keratinocytes and that additional functions of the p53 protein other than transcriptional regulation of the p21CIP1/WAF1 gene are required for p53 mediated tumor suppression.