UVA-Induced MAPK Signaling

Ultraviolet radiation is the most important environmental carcinogen leading to the development of skin cancers. UV irradiation can cause DNA and protein damage. The carcinogenesis of UV is caused by a deficit in pyrimidine dimers repair pathway or UV induced MAPK pathway disorder. UV radiation (100 - 400 nm) is divided into at least three different categories based on wavelength: Ultraviolet-A(UVA), UVB and UVC. UVA is the major component (about 95%) of the UV that reaches the earth's surface. Cells damaged by UVA normally undergo apoptosis; failed apoptosis plays an important role in tumor development. UVA irradiation affects cellular signaling mechanisms and is known to cause the activation of stress-related kinases including all the three MAPKs i.e. ERK, JNK, and p38. STAT1 is an example of a TF that can be phosphorylated and activated by JNK, p38 MAPK and ERK in response to UVA. UVA stimulation of the MAPK pathways are mediated either through EGFR or may be EGFR independent. UVA activation of EGFR leads to the phosphorylation of p70S6K and p90RSK. Activation of ERKs and JNKs, but not of p38 kinase, are involved in UVA-induced p90RSK activation and phosphorylation at Ser381. p90RSK is a member of the family of 90-kD ribosomal S6 kinases that plays key role in proliferation, differentiation, and apoptosis. SMase is another important enzyme whose activity is increased in response to UVA exposure.UVA can activate ERK through PKC in a Ras-dependent pathway that requires PLC and calcium. Interestingly, UVA activated p38 MAPK increases the expression of the Bcl-XL, anti-apoptotic Bcl2 family member. Inhibition of p38 MAPK decreases expression of Bcl-XL and results in mitochondrial permeabilization through release of cytochrome-C, cleavage of initiator caspases (8 and 9), the effector caspase (3), as well as the apoptotic substrate PARP. UVA mediated increase in Bcl-XL is through a post-transcriptional mechanism involving the 3'-UTR. Solar UV irradiation can cause three most common skin cancers those include basal cell carcinomas, squamous cell carcinomas and cutaneous malignant melanomas.