Multiple melanoma susceptibility factors function in an ultraviolet radiation response pathway in skin.

Abstract

Exposure to ultraviolet radiation (UVR) and the familial melanoma susceptibility gene p16 (CDKN2A) are among the major risk factors which have been identified to contribute to the development of melanoma, and also significantly contribute to squamous cell carcinoma. We have previously shown that UVR induces p16(CDKN2A) expression in melanoma and keratinocyte cell lines and human skin, but the regulatory mechanisms controlling this expression are unknown. To determine the mechanism by which UVR induces p16(CDKN2A) expression in melanocytes and keratinocytes in the epidermis. We have used an in vitro cell lines model of the UVR response in skin to assess the changes in p16(CDKN2A) expression and the signalling pathways regulating these changes, and validated these findings in whole human skin cultures. We show that UVR-induced ERK signalling, mediated by BRAF, regulates p16(CDKN2A) expression at the transcriptional, and possibly translational level. This study demonstrates the biological connection between the known melanoma genes p16 (CDKN2A) and BRAF in a normal physiological response to UVR in the skin, and highlights the importance of defects in this biological pathway to melanoma and squamous cell carcinoma development.