UVC-Induced MAPK Signaling

UV radiation is a naturally occurring genotoxic agent and is the primary environmental carcinogen responsible for the development of most skin cancers. UV radiation is composed of UVC (200-280 nm), UVB (280-315 nm) and UVA (315-400 nm). Since the ozone layer blocks most UVC exposure, UVA and UVB are probably the chief carcinogenic components of sunlight that are relevant for human skin cancer. DNA is known to be an important target for the mutagenic and carcinogenic effects of UV irradiation. In addition to DNA damage, alterations in signaling molecules caused by UV irradiation result in distorted gene expression.The MAPK signaling cascades are targets for UV and are important in the regulation of a multitude of UV-induced cellular responses. UVC stimulates all three MAPK pathways as also transcription factors like c-Jun and c-Fos. While UVC does have specific effects in cells, it has signaling components in common with responses to UVA and UVB irradiation, including EGFR, PKC, AP-1, ATR, and p53. Therefore it is difficult to delineate specific effects of UVC. UVC acts through EGFR or PKCs, both of which then activate a MAPK cascade. This results in diverse responses, including cell proliferation, tumor promotion and apoptosis. UVC-induced AP-1 activation occurs through Src, followed by the Ras/Raf/MEK/ERK pathway. UVC also stimulates SMase, and enzyme that catalyzes the hydrolysis of ceramide. Ceramide acts as a modulator of various stress-related responses, including cell cycle arrest, cell senescence, and apoptosis. Unlike UVA, UVC exposure does not activate ATM. It stimulates ATR, a kinase that is structurally and functionally similar to ATM. ATR may function as a sensor of DNA damage in response to UVC. In cell lines like JB6 and the human breast cancer cell line MCF-7, p38 kinase directly phosphorylates p53 in response to UVC. UVC also interacts directly with DNA, causing the formation of cyclobutane pyrimidine dimers or 6-4 photo-products, these are believed to be a major component of the DNA damage resulting from UV exposure.