SKIN CANCER--ROLE OF UVB INDUCED CELL CYCLE ALTERATIONS

Nonmelanoma skin cancer (NMSC) accounts for almost half of all forms of cancer and is particularly problematic in the elderly. Epidemiologic evidence indicates that exposure to sunlight is the major risk factor for NMSC. Solar ultraviolet (UV) radiation is capable of producing structural alterations in DNA that evoke mutagenic change that culminate in tumor formation. Recently it has become clear that cell cycle regulators are the last step in the cascade controlling cell proliferation and may provide the bridge between cancer cell physiology, molecular biology, and environmentally induced cancer. The hypothesis to be tested is that skin exposure to UVB radiation causes mutagenic change, affecting the tumor suppressor gene, p53, and that these mutations result in profound alterations in the regulation of the cell cycle that are crucial for the induction of skin cancer. An integrated approach will employ cell culture systems and murine models for cutaneous cancer. Photocarcinogenesis studies will be conducted in SKH/1 hairless mice and a series of keratinocyte populations derived from these animals in an effort to correlated in vitro effects with UVB- induced carcinogenesis. Studies will also utilize normal human keratinocytes and transformed keratinocyte lines derived from epidermoid carcinomas that harbor P53 mutations.