UVA-Induced MAPK Signaling
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UVA-Induced MAPK Signaling

Solar UV (Ultraviolet) irradiation is the most important environmental carcinogen leading to the development of skin cancers. UV irradiation can cause DNA and protein damage, which in part accounts to oxidative damage. The carcinogenesis of UV is caused by deficit in pyrimidine dimers repair pathway or UV induced MAPK pathway disorder.  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).  UVA has the longest wavelength (315-400 nm), lowest energy (3.1-3.9 eV) and UVC has the shortest wavelength (200-280 nm), highest energy (4.3-6.5 eV). UVA is the major component (about 95%) of the UV part of sunlight that reaches the Earths surface. Recently UVA has been listed as a reasonably anticipated human carcinogen. Cells damaged by UVA normally undergo Apoptosis; failed Apoptosis plays an important role in Tumor development (Ref.1). UVA irradiation affects cellular signaling mechanisms and is known to cause the activation of transcription factors such as NF-KappaB (Nuclear Factor Kappa-B) and the Stress-related kinases including all the three MAPKs (Mitogen Activated Protein Kinases) i.e. ERK (Extracellularly Regulated Kinase), JNK (c-Jun N-terminal Kinase), and p38. UVA causes oxidative stress in cells via the formation of ROS (Reactive Oxygen Species) including singlet Oxygen and H2O2 (Hydrogen Peroxide), which besides damaging other cellular constituents, can initiate lipid peroxidation in membranes (Ref.2).

UVA stimulation of the MAPK pathways are mediated either through EGFR (Epidermal Growth Factor Receptor) or may be EGFR independent. UVA exposure is associated with the production of ROS, including H2O2. H2O2 may activate the EGFR by inducing its phosphorylation, which then leads to the activation of a complex network of downstream effector molecules, including the phosphorylation of the 40S ribosomal protein S6 by p70S6K (70-kD ribosomal S6 kinase) and p90RSK (90-kD ribosomal S6 kinase, also known as MAPKAPK1) via PI3K (Phosphatidylinositde-3 Kinase). p90RSK is a member of the family of 90-kD ribosomal S6 kinases, which is involved in signal transduction leading to proliferation, differentiation, and apoptosis. The ribosomal S6 kinases appear to mediate translation through the multiple phosphorylation of the 40S ribosomal protein S6. Activation of ERKs and JNKs, but not of p38 kinase, is involved in UVA-induced p90RSK activation and phosphorylation at Ser381. ERK, but not JNK or p38 kinase, signaling to p70S6K or p90RSK may be stimulated by the EGFR after UVA exposure. Thus, UVA-induced EGFR signaling is required for activation of p70S6K and p90RSK through the PI3K and ERKs pathways, but not for activation by the JNK or p38 kinase pathways. An increased activation of basal and EGF-inducible MAPK, p90RSK, and p70S6K is associated with the activation of AP-1 (Activator Protein-1) i.e. Jun or Fos in tumor promotion and in tumor promoter-induced cell transformation (Ref.3).

Two important proteins whose activities are increased in response to UVA exposure are, the kinase that is responsible for Ataxia Telangiectasia, called ATM (Ataxia Telangiectasia Mutated Gene), and SMase (Sphingomyelinase). ATM is a member of the PI3K family and is a serine-threonine protein kinase with a COOH-terminal domain similar to the catalytic subunit of PI3K. ATM plays a vital role in multiple signal transduction pathways leading to p53 activation in response to DNA damage. ATM is activated by UVA exposure and is involved in the cellular decision to trigger p53- and JNK-dependent apoptosis in response to UVA. Acid SMase is also activated by UVA. Exogenous SMase and its product, Ceramide, also induce apoptosis independent of activation of intracellular SMase, but induction of apoptosis by SM (Sphingomyelin) is dependent on the SMase activity. 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 (Ref.4).

ERK activation by UVA is also mediated by PKC (Protein Kinase-C) in a Ras-dependent pathway that requires PLC (Phospholipase-C) and Ca2+ (Calcium) but not the EGFR Kinase activity. The mechanisms involved in UVA-induced PLC activation are not yet clear. The sustained increase in intracellular Ca2+ level serve as an indicator of sustained PLC activation and a cofactor for PKC-Alpha activation after UVA radiation. Activation of ERK inhibits the activation of Caspase8 and BID (BH3 Interacting Domain Death Agonist). ERK activation also inhibits Caspase9 activity by direct phosphorylation at Thr125, which is sufficient to block Caspase9 processing and subsequent Caspase3 activation (Ref.3). Inhibition of Caspases8 and -9 by ERK promotes cell survival and contribute to Tumorigenesis when the ERK pathway is constitutively activated. Inhibition of p38 MAPK decreases expression of BclXL (Bcl2 Related Protein Long Isoform) and results in the mitochondrial permeabilization through release of CytoC (Cytochrome-C), cleavage of initiator Caspases (Caspase8 and Caspase9), the effector Caspase (Caspase3), as well as the apoptotic substrate PARP (Poly ADP-Ribose Polymerase). UVA results in increase in the anti-apoptotic Bcl2 (B-Cell CLL/Lymphoma-2) family member, BclXL, through a post-transcriptional mechanism involving the 3-untranslated region (3-UTR) (Ref.5 and Ref.6).

UVA-induced MAPK signaling pathways also lead to STAT1 (Signal Transducer and Activator of Transcription-1) Ser727 phosphorylation. UVA-induced Ser727 phosphorylation of STAT1 is diminished by PD98059 and U0126, two specific inhibitors of MEKs, and SB202190 and PD169316, inhibitors of p38 kinase and JNKs respectively. STAT1 phosphorylation is also blocked by a JNK1- or JNK2-deficiency or an N-terminal or C-terminal kinase-dead mutant of MSK1 (Mitogen- and Stress-Activated Protein Kinase-1), a downstream kinase closer to p38 kinase and ERKs. Thus, Phosphorylation of STAT1 at Ser727 occurs through diverse MAPK cascades including MEK1 (MAPK/ERK Kinase-1), ERKs, p38 kinase, JNKs and MSK1 in the cellular response to UVA. Solar UV irradiation is involved in the development of the three most common skin cancers. These are the nonmelanocytic skin cancers that include BCCs (Basal Cell Carcinomas), SCCs (Squamous Cell Carcinomas), and CMMs (Cutaneous Malignant Melanomas). The MAPK signaling cascades are important targets for UV and are important in the regulation of the multitude of UV-induced cellular responses. The mechanism of carcinogenesis caused by disorder of this pathway is still under research (Ref.7).