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Loss of p21CIP1/WAF1 does not recapitulate accelerated malignant conversion caused by p53 loss in experimental skin
W C Weinberg1, N E Montano, C Deng
1Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
The p53 tumor suppressor protein
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The p53 protein is a key tumor suppressor.
- p21(CIP1/WAF1) is a downstream target of p53.
- p53-null cells show altered growth and differentiation.
Purpose of the Study:
- To investigate if p21(CIP1/WAF1) mediates p53's tumor suppressor functions.
- To determine the role of p21(CIP1/WAF1) gene dose in v-ras(Ha) oncogene-driven keratinocyte transformation.
- To assess the impact of p21(CIP1/WAF1) on tumor differentiation and growth.
Main Methods:
- Primary keratinocytes with varying p21(CIP1/WAF1) gene doses were used.
- Cells were transduced with the v-ras(Ha) oncogene.
- Transduced cells were grafted onto nude mouse hosts for in vivo tumor formation and analysis.
Main Results:
- Tumor differentiation and malignant progression were similar across different p21(CIP1/WAF1) genotypes.
- p21(CIP1/WAF1)-deficient keratinocytes expressing v-ras(Ha) did not exhibit the same accelerated growth as p53-deficient tumors.
- These cells showed less altered responsiveness to calcium-induced growth inhibition compared to p53-deficient counterparts.
Conclusions:
- p21(CIP1/WAF1) does not mediate the effects of p53 on keratinocyte differentiation or malignant progression.
- p53 likely exerts its tumor suppressor functions through additional mechanisms beyond p21(CIP1/WAF1) regulation.
- These findings highlight the complex role of p53 in tumor suppression.