UV (Ultraviolet) radiation is a naturally occurring genotoxic agent and is the primary environmental carcinogen responsible for the development of most skin Cancers. The UV portion of solar radiation is composed of UVC (200-280 nm), UVB (280-315 nm), and UVA (315-400 nm). Much of the important damage produced by solar radiation is caused by UVB fluences, which induce damage to a variety of cellular targets including DNA. In the case of DNA damage, UVB generates Oxygen radicals as well as inducing Cyclobutane pyrimidine dimers and Pyrimidine-Pyrimidone photoproducts. These forms of DNA damage, directly or indirectly, signals the activation of a series of signal transduction cascades comprised of serine/threonine kinases, MAPKs (Mitogen-Activated Protein Kinases). In addition, UV radiation rapidly triggers signal transduction pathways involving the MAPKs by activation of Growth Factor Receptors and other non-nuclear targets (Ref.1).
UVB stimulates JNKs (c-Jun N-terminal Kinase), p38 kinase, and ERKs (Extracellularly Regulated Kinase) through the EGFR (Epidermal Growth Factor Receptor), PKC (Protein Kinase-C), 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 human Keratinocyte cell line. In proliferating human epidermal keratinocytes, UVB exposure stimulates phosphorylation of JNKs and p38
kinase. UVB (4000 J/m2) stimulates the phosphorylation of p38
kinase and JNKs, but not ERKs, and that p38
kinase appears to mediate Apoptosis induced by UVB (Ref.2).
UVB induced MAPKs activates c-Jun and c-Fos i.e. AP-1 (Activator Protein-1). Activation of AP-1 does not involve the EGFR. Instead, UVB-induced AP-1 activation involves aPKCs
(atypical PKCs). UVB-induced signaling pathways also leads to stabilization and phosphorylation of p53, with JNKs as direct signaling mediators of UVB-induced p53 phosphorylation at Ser20. ERKs
and p38 kinase are involved in UVB-induced phosphorylation of p53 at Ser15. JNK-mediated Ser20 phosphorylation of p53 was associated with p53-dependent transcriptional activation and Apoptosis (Ref.3). Besides p53, UVB stimulates BAD (Bcl2-Antagonist of Cell Death) phosphorylation at Ser112, which is mediated through MAPK signaling pathways in which JNK1, RSK2 (p90 Ribosomal S6 Kinase-2), and MSK1 (Mitogen- and Stress-activated Protein Kinase-1) are direct mediators. BAD is a member of the Bcl2 (B-Cell CLL/Lymphoma-2) family of Apoptosis-related proteins. Some members, including Bcl2 and BclXL (Bcl2 Related Protein Long Isoform), promote cell survival, whereas other members, including BAD, BID (BH3 Interacting Domain Death Agonist), BAX (Bcl2 Associated-X Protein), and BAK (Bcl2 Antagonist Killer) promote cell death. Phosphorylation of BAD at Ser112 and Ser136 results in its dissociation from pro-survival BclXL. This dissociation leads to protection from Apoptosis. Regulation of p53 and BAD are two mechanisms by which UVB irradiation can result in Apoptosis (Ref.4).
UVB stimulates phosphorylation of H3 (Histone-3) at Ser10, and ERKs and p38
kinase mediate this phosphorylation. UVB also stimulates phosphorylation of H3 at Ser28, and ERKs, p38
kinase, and JNKs contribute to this phosphorylation event. MSK1, a downstream kinase of p38 and ERK MAPKs, mediates the UVB-induced phosphorylation of H3 at Ser28 (Ref.5). UVB also activates the PI3K pathway, which initiates activation of a diverse group of signaling molecules, including Akt (v-Akt Murine Thymoma Viral Oncogene) and p70S6K (70-kD ribosomal S6 kinase). These effects are mediated by ERKs and p38 kinase, but not by JNKs. MSK1 are also involved in Akt activation. UVB stimulates the phosphorylation of 4EBP1 (Eukaryotic Translation Initiation Factor-4E-Binding Protein-1) through the p38 Kinase-to-MSK1 pathway, presumably facilitating its dissociation from eIF4E (Eukaryotic Translation Initiation Factor-4E), presumably having a positive effect on cap-dependent initiation of translation. Phosphorylation of 4EBP1 also occurs via mTOR (Mammalian Target of Rapamycin) (Ref.4 and Ref.6). Thus, UVB radiation causes a variety of biological effects that can be either beneficial or harmful for human health. UVB induces a variety of signaling pathways, which act in an independent and additive ways. Excessive exposure of solar UV radiation, particularly its UVB component, to humans causes many adverse effects that include Erythrma, Hyperplasia, Hyperpigmentation, Immunosuppression, Photoaging and Skin Cancer (Ref.7).