Loss of p21(CIP1/WAF1) does not recapitulate accelerated malignant conversion caused by p53 loss in experimental skin carcinogenesis

被引:23
作者
Weinberg, WC [1 ]
Montano, NE [1 ]
Deng, C [1 ]
机构
[1] NIDDKD,BIOCHEM & METAB LAB,NIH,BETHESDA,MD 20892
关键词
p53; p21(CIP1/WAF1); epidermal carcinogenesis;
D O I
10.1038/sj.onc.1201230
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The p21(CIP1/WAF1) protein is considered a downstream effector of tumor suppression by p53, We have previously demonstrated that p53 null keratinocytes have lower basal p21(CIP1/WAF1) mRNA levels and that tumors derived from these cells following transduction with the v-ras(Ha) 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 p21(CIP1/WAF1) gene dose were 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 differentiated papillomas; focal carcinomas were observed in 43, 30 and 44% of papillomas derived from +/+, +/- and -/- keratinocytes, respectively, p21(CIP1/WAF1) deficient keratinocytes expressing v-ras(Ha) do not display the degree of increased growth observed in p53 deficient tumors irt vivo or the decreased responsiveness to negative growth regulation by Ca2+ in vitro. These results suggest that p21(CIP1/WAF1) does not regulate the differentiated phenotype or malignant progression of v-ras(Ha) initiated keratinocytes and that additional functions of the p53 protein other than transcriptional regulation Of the p21(CIP1/WAF1) gene are required for p53 mediated tumor suppression.
引用
收藏
页码:685 / 690
页数:6
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