UVC-Induced MAPK Signaling
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UVC-Induced MAPK Signaling

UV (Ultraviolet) irradiation is a component of sunlight, which has higher energy than visible light. UV radiation (100 and 400 nm) is divided into at least three different categories based on wavelength: UVA (Ultraviolet-A) , UVB (Ultraviolet-B) and UVC (Ultraviolet-C).  UVC wavelengths (100-280 nm) are very strongly affected by ozone levels, so that the levels of UVC radiation reaching the earth’s surface are relatively small. Because the ozone layer blocks UVC exposure, UVA (UVA I, 340-400 nm; UVA II, 320-340 nm) and UVB (280-320 nm) are probably the chief carcinogenic components of sunlight with relevance for human skin cancer. DNA is known to be an important target for the mutagenic and carcinogenic effects of UV irradiation (Ref.1). In addition to DNA damage, alterations in signaling molecules caused by UV irradiation result in distorted gene expression. The MAPK (Mitogen-Activated Protein Kinase) signaling cascades are targets for UV and are important in the regulation of the multitude of UV-induced cellular responses. UVC is the best-studied form of UV radiation, but is least relevant to the human condition. Insights gained from UVC-induced signaling pathways still contribute to overall understanding of the signaling pathways leading to UV-induced skin carcinogenesis. UVC stimulates all three MAPK pathways including ERK (Extracellularly Regulated Kinase), JNK (c-Jun N-terminal Kinase), and p38, and activates c-Jun and c-Fos, but with exceptions. Although UVC does have specific effects in cells, there are signaling components common to those implicated in responses to UVA and UVB irradiation, including EGFR (Epidermal Growth Factor Receptor), PKC (Protein Kinase-C), AP-1, ATR (Ataxia-Telangiectasia and Rad3 Related), and p53 Ref.2).

UVC acts through the EGFR or PKCs or both to activate the MAPKs cascades, which results in diverse responses, including cell proliferation, tumor promotion, and apoptosis. In HeLa cells, UVC-induced AP-1 activation occurs through Src (v-Src Avian Sacroma (Schmidt-Ruppin A-2)Viral Oncogene), Ras, Raf (v-Raf1 Murine Leukemia Viral Oncogene), and Growth Factor Receptors, including the EGFR. This well characterized cascade is initiated by Growth Factor binding, which stimulates RTKs (Receptor Tyrosine Kinases). The sequential activation of the GTP-binding protein Ras and the Serine kinase Raf then ensues. Raf then activates MEK (MAPK kinase), a threonine/tyrosine dual specificity kinase that directly activates ERKERK translocates in the nucleus and activates transcription factors Elk1 (ETS-domain protein Elk1), Myc (v-Myc Avian Myelocytomatosis Viral Oncogene Homolog), Jun (v-Jun Avian Sarcoma Virus-17 Oncogene) and Fos (v-Fos FBJ (Finkel-Biskis-Jinkins) Murine Osteosarcoma Viral Oncogene Homolog). Interaction between Fos and Jun leads to the transcription complex AP-1 (Activator Protein-1), which switches on a number of genes associated with cell growth and differentiation (Ref.3 and Ref.4). In JB6 cells, PKC and not the EGFR, mediates UVC-induced AP-1 activation. In JB6 and lens epithelial cells, UVC activation of p38 kinase and JNKs appeared to occur independently of PKC. In human epidermoid carcinoma A431 cells, UVC stimulated ERKs through the tyrosine phosphorylation and activation of the EGFR. Inhibition of the EGFR or ERK activation results in an increase in UV-induced apoptosis, suggesting that the UVC activation of ERKs through the EGFR serves as a protective or survival mechanism. In addition to ERKs, JNKs are also activated by UVC exposure. UVC also induces a direct phosphorylation of ATF2 (Activating Transcription Factor-2) by ERKs or MSK1 (Ref.5).

UVC also stimulate activation of SMase (Sphingomyelinase). Stimulation of SMase leads to hydrolysis of Ceramide, which can act as a modulator of various stress-related responses, including cell cycle arrest, cell senescence, and apoptosis. These responses can stimulate phosphorylation and activation of JNKs. Unlike UVA, UVC exposure does not activate ATM (Ataxia Telangiectasia Mutated Gene). Instead, UVC 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. ATR is required for UVC-induced JNKs and p53 signaling leading to apoptosis. In JB6 cells, UVC phosphorylates p53 at Ser389 by p38 kinase. In the human breast cancer cell line MCF-7, p38 kinase directly activates and phosphorylates p53 at Ser33 and Ser46 in response to UVC. p38 kinase has a major role in mediating the phosphorylation of p53, leading to UVC-induced apoptosis. UVC also interact directly with DNA, causing the formation of cyclobutane pyrimidine dimers or 6-4 photoproducts. Although UV irradiation can produce various types of damage, cyclobutane pyrimidine dimers or 6-4 photoproducts are believed to be the major type of DNA damage resulting from UV exposure. Because of the ring structure of its bases, DNA absorbs UV photons very efficiently. DNA damaged by UV is normally repaired by a nucleotide excision repair mechanism. However, if the damaged bases are not repaired or are incorrectly repaired, this can lead to mutations and subsequent carcinogenesis (Ref.6).