Cell cycle regulatory proteins in UVB-skin carcinogenes

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DESCRIPTION (provided by applicant): Basal Cell and squamous cell carcinomas (nonmelanoma skin cancers or NMSC) are the most common type of human malignancies with approximately one million new cases diagnosed annually in the United States. The vast majority of these tumors are the result of exposure to sunlight, particularly ultraviolet B (UVB) radiation. It is becoming increasingly clear that cell cycle regulators, including cyclin Dl, are potential targets for UVB-induced damages. We demonstrated that UVB irradiation of a transformed keratinocyte cell line lacking functional p53 results in cell cycle arrest in GI. This arrest coincided with the degradation of cyclin Dl and cdk4 proteins and was, in part, proteasome-dependent. This suggests that regulation of cyclin Dl protein stability is an early cellular response to UVB radiation. Furthermore, increased levels of cyclin Dl are found in various types of tumors. Indeed, our complete photocarcinogenesis study in a mouse model showed the early accumulation of cyclin Dl protein that increased gradually during UVB-induced skin carcinogenesis. Thus, regulation of cyclin Dl stability seems to be a key event of the short- and long-term responses to UVB radiation. We propose to study the mechanisms regulating cyclin Dl stability following U\JB radiation in cell lines and in mouse models for skin photocarcinogenesis. We will test the hypothesis that the mechanism(s) responsible for the rapid UVB-induced degradation of cyclin Dl are impaired in skin chronically exposed to UVB, thus participating in the accumulation of cyclin Dl leading to skin tumors formation. We anticipate that the combination of in vitro and in vivo approaches will help to better understand the molecular basis of skin cancer development. In addition, our studies could provide a rationale to develop new therapeutic tools targeted towards the protein degradation machinery.