Activation of p38 MAP kinase and JNK pathways by UVA irradiation

Abstract

There are more than two million new cases of non-melanoma skin cancers (NMSCs) diagnosed each year in the United States. The clear etiological factor is chronic exposure to solar radiation from the sun. The wavelengths of solar light that reach the earth’s surface include UVB (280-320nm) which accounts for 1-10% and UVA (320-400nm) which accounts for 90-99% of the radiation. While most of the published research has focused on the effects of UVB, little is known concerning UVA-mediated signal transduction pathways and their role in skin tumor promotion and progression giving rise to squamous cell carcinomas (SCCs). Here we have focused on UVA-mediated activation of p38 MAP kinase and c-Jun N-terminal kinase (JNK) and their roles in activator protein-1 (AP-1) mediated transcription, cyclooxygenase-2 (COX-2) and Bcl-XL expression. Since p38 MAP kinase and JNK play major roles in the expression of UVA-induced AP-1, COX-2 and Bcl-XL, pharmacological inhibitors of these kinases may be useful in the chemoprevention of SCC skin cancer.

Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts

“…Among the lipid photoproducts that we and others detected here but also earlier are mediators that promote pro-inflammatory signaling: Oxidized PAPC can induce p38 MAPK signaling that in turn leads to expression of COX-2 [40] and p38 MAPK is essential for COX-2 expression in response to UV [55]. Platelet activating factor (PAF) -like lipids that were identified as important signaling photoproducts can promote TNF alpha synthesis upon UV exposure [56].…”

Interleukin‐1β enhances cell migration through AP‐1 and NF‐κB pathway‐dependent FGF2 expression in human corneal endothelial cells

“…Correspondingly, migration of human CEC was dramatically enhanced following treatment with either IL-1β or FGF2, and this could be completely abolished by co-treatment with SU5402, a pan FGF antagonist, or IL-1Ra (Figure 1C). Because p38 works as an upstream regulator for AP-1 (Lin et al, 2009; Kook et al, 2011; Zhang and Bowden, 2012) and because activation of NF-κB is mediated by IKK phosphorylation (Kim et al, 2006; Hayden and Ghosh, 2008) in various cell types, we used ELISA to investigate whether IL-1β stimulation results in AP-1 and NF-κB activation in human CEC. Both AP-1 and NF-κB activities were greatly induced by IL-1β, and co-treatment with IL-1Ra nearly extinguished the IL-1β dependent activation of AP-1 and NF-κB in human CEC (Figure 1D).…”

Molecular signaling cascades involved in nonmelanoma skin carcinogenesis

“…The pathophysiological effect of UVR-induced activation of both p38 and JNK in keratinocytes is controversial, as reports show that these stress response proteins can elicit both pro- and anti-survival mechanisms [104]. However, given the bimodal role that oxidative stress plays in cancer, this seemingly contradictory response is not surprising.…”

“…Other reports indicate that UVR-induced p38 activation induces NOXA-dependent apoptosis through increased protein expression of hypoxia-inducible factor 1-alpha (HIF-1α) in a p53-independent manner [114]. In contrast, it has been shown that p38 activation increases UVR-induced survival of keratinocytes though upregulation of the cancer associated genes Bcl-XL and COX-2 [104]. Activation of p38 can also directly phosphorylate glycogen synthase kinase 3 beta (GSK3β) at Thr 43 and Thr 390 (Ser 389 in mice), which promotes β-catenin dependent growth and proliferation [115].…”