Weinberg W C, Montano N E, Deng C
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Oncogene. 1997 Aug 7;15(6):685-90. doi: 10.1038/sj.onc.1201230.
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 in 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.
p21（CIP1/WAF1）蛋白被认为是p53肿瘤抑制作用的下游效应分子。我们之前已经证明，p53基因缺失的角质形成细胞的基础p21（CIP1/WAF1）mRNA水平较低，并且这些细胞在用v-ras（Ha）癌基因转导后形成的肿瘤比野生型角质形成细胞生长得更快，并迅速发展为未分化癌（《癌症研究》54：5584 - 5592，1994）。在本研究中，用编码v-ras（Ha）的逆转录病毒转导具有不同p21（CIP1/WAF1）基因剂量的原代角质形成细胞，并将其移植到裸鼠宿主中，以测试p53基因缺失表型是否通过p21（CIP1/WAF1）介导。所有基因型产生的肿瘤均为高分化乳头状瘤；在分别源自+/+、+/-和-/-角质形成细胞的乳头状瘤中，分别有43%、30%和44%观察到局灶性癌。表达v-ras（Ha）的p21（CIP1/WAF1）缺陷角质形成细胞在体内未表现出p53缺陷肿瘤中观察到的生长增加程度，在体外也未表现出对Ca2+负生长调节的反应性降低。这些结果表明，p21（CIP1/WAF1）不调节v-ras（Ha）引发的角质形成细胞的分化表型或恶性进展，并且p53介导的肿瘤抑制需要p53蛋白除了对p21（CIP1/WAF1）基因的转录调控之外的其他功能。
