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

Oncogene. 1997 Aug 7;15(6):685-90. doi: 10.1038/sj.onc.1201230.

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.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics*
  • Fibroblasts
  • Gene Dosage
  • Genes, ras
  • Immunohistochemistry
  • Keratinocytes / transplantation
  • Keratinocytes / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Papilloma / genetics
  • Papilloma / metabolism
  • Retroviridae / genetics
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / pharmacology
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Calcium