UVB-Induced MAPK Signaling


Pathway Description

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). A significant amount of damage produced by solar radiation is caused by UVB, which induces damage to a variety of cellular targets including DNA. In the case of DNA damage, UVB generates oxygen radicals as well as induces cyclobutane pyrimidine dimers and pyrimidine-pyrimidone photo-products. These forms of DNA damage, directly or indirectly, activate a series of signal transduction cascades comprised of serine/threonine kinases and MAPKs.

UVB stimulates JNKs, p38 MAPK and ERKs through the EGFR, PKC, or both, leading to varied responses. These responses vary depending on cell type and exposure dose. UVB (100 to 800 J/m2) stimulates a strong activation of JNKs, but weakly stimulates ERKs in a human keratinocyte cell line. In proliferating human epidermal keratinocytes, UVB exposure stimulates phosphorylation of JNKs and p38 MAPK. UVB (4000 J/m2) stimulates the phosphorylation of p38 MAPK and JNKs, but not ERKs. UVB induced MAPKs activate c-Jun and c-Fos (AP-1). Activation of AP-1 does not involve the EGFR. Instead, UVB-induced AP-1 activation involves atypical PKCs. UVB-induced signaling pathways also lead to stabilization and phosphorylation of p53. JNKs mediate UVB-induced p53 phosphorylation at Ser20 while p38 MAPK is involved in UVB-induced phosphorylation of p53 at Ser15. UVB also stimulates BAD phosphorylation at Ser112, which is mediated through MAPK signaling pathways in which JNK1, RSK2, and MSK1 are direct mediators. BAD is a member of the Bcl2 family which is involved in cell survival. UVB can phosphorylate H3 at Ser10 through p38 MAPK. UVB stimulates the phosphorylation of 4EBP1 via mTOR, facilitating its dissociation from eIF4E. This may have a positive effect on cap-dependent initiation of translation. Thus, UVB radiation affects a variety of biological effects.


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