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Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892
Epidermal keratinocyte cultures were established from newborn mice expressing a null mutation in the p53 gene to explore the contribution of p53 to epidermal growth regulation and neoplasia. Keratinocytes were initiated by transduction with a replication-defective retrovirus encoding the v-rasHa oncogene and grafted onto nude mouse hosts. Tumors arising from keratinocytes heterozygous or null for functional p53 in the presence of v-rasHa have growth rates approximately 5-fold higher than those derived from p53(+/+) controls and rapidly form carcinomas, in contrast to the benign phenotype observed in p53(+/+)/v-rasHa grafts. In vitro,p53-deficient keratinocytes with and without v-rasHa expression display decreased responsiveness to the negative growth regulators transforming growth factors ß1 and ß2. In combination with v-rasHa, p53-deficient keratinocytes also exhibit decreased responsiveness to elevated Ca2+. These differences between genotypes cannot be attributed to changes in transforming growth factor ß receptor types present or altered levels of epidermal growth factor receptor and are independent of c-myc transcript levels. mRNA expression for the p-53 inducible protein WAF1 correlates with p53 gene dosage, but low levels are still detectable in p53(-/-) keratinocytes. The altered responsiveness of p53 deficient keratinocytes to negative growth regulators may provide a growth advantage to such cells in vivo and render them more susceptible to genetic alterations and malignant conversion.
1 To whom requests for reprints should be addressed, at Building 37, Room 3B25, National Cancer Institute, Bethesda, MD 20892.
2 C. G. A. is a Howard Hughes Medical Institute-NIH Research Scholar.
Received 4/27/94. Accepted 9/ 1/94.
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