The p53 tumor suppressor gene is mutated or inactivated in a majority of human cancers. Our studies have focused on elucidating the function and mechanism of action of this gene product in normal keratinocyte biology and neoplasia. We have utilized keratinocytes of murine epidermis and both in vitro and in vivo approaches to dissect the stages of differentiation and neoplastic progression in this squamous epithelium. The cyclin dependent kinase inhibitor WAF1, a downstream target of p53 mediated gene transcription, is believed to be an effector of tumor suppression by p53. Using mice genetically engineered to harbor a null mutation in the WAF1 gene, we have demonstrated that loss of WAF1 is not sufficient to explain the malignant phenotype of p53 null tumors. Thus other features of p53 beside transcriptional activation of the WAF1 gene are necessary for its tumor suppressor function. In addition, by differential display analysis we have identified a novel p53 regulated gene that is also part of the TNF-alpha pathway and have found that this over-expression of this gene product rapidly induces keratinocyte cell death.
| Ponnamperuma, Roshini M; King, Kathryn E; Elsir, Tamador et al. (2009) The transcriptional regulatory function of p53 is essential for suppression of mouse skin carcinogenesis and can be dissociated from effects on TGF-beta-mediated growth regulation. J Pathol 219:263-74 |
