UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53

Abstract

Human keratinocytes respond to UV rays by developing a fast adaptive response that contributes to maintaining their functions and survival. We investigated the role of the mitogen-activated protein kinase pathways in transducing the UV signals in normal human keratinocytes. We found that UVA, UVB or UVC induced a marked and persistent activation of p38, whereas c-Jun N-terminal kinase or extracellular signal-regulated kinase were less or not activated respectively. Inhibition of p38 activity by expression of a dominant-negative mutant of p38 or with SB203580 impaired cell viability and led to an increase in UVB-induced apoptosis. This sensitization to apoptosis was independent of caspase activities. Inhibition of p38 did not sensitize transformed HaCaT keratinocytes to UVB-induced apoptosis. In normal keratinocytes, expression of a dominant-negative mutant of p53 increased UVB-induced cell death, pointing to a role for p53. In these cells, UVB triggered a p38-dependent phosphorylation of p53 on Ser-15. This phosphorylation was associated with an SB203580-sensitive accumulation of p53, even in the presence of a serine phosphatase inhibitor. Accumulated p53 was localized mainly in the cytoplasm, independently of CRM1 nuclear export. In HaCaT cells, p53 was localized exclusively in the nucleus and its distribution and level were not affected by UVB or p38 inhibition. However, UVB induced an SB203580-insensitive phosphorylation on Ser-15 of mutated p53. Overall, our results suggest that, in normal human keratinocytes, protection against UVB depends on p38-mediated phosphorylation and stabilization of p53 and is tightly associated with the cytoplasmic sequestration of wild-type p53. We conclude that the p38/p53 pathway plays a key role in the adaptive response of normal human keratinocytes against UV stress.

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…More specifically, UVB-damaged keratinocytes release U1 spliceosomal non-coding RNA that activates TLR3 in non-irradiated cells, resulting in the release of inflammatory cytokines, such as TNF-α and IL-6 [49]. These effects are consistent with findings from earlier studies, showing that UV-radiation activated NF-κB [50], triggered the pro-inflammatory MAPK p38 and c-Jun N-terminal kinase signalling arms [51][52][53], and promoted IL-6 and TNF-α release [54,55]. In light of subsequent studies on U1 RNA-mediated TLR3 activation, it seems likely that this pathway is involved in initiating these UVB-triggered inflammatory responses.…”

Raman spectroscopic mapping for the analysis of solar radiation induced skin damage

“…Solar UV radiation is implicated in the induction of both malignant melanomas and non-melanoma skin cancer 34,35 . Solar UV radiation is also known to induce cellular and genomic toxicity, reactive oxygen species (ROS) formation, DNA damage, sunburnt cells and higher proteolytic rates [36][37][38][39][40][41][42][43] . If the cellular repair and antioxidant responses to UV radiation are overwhelmed, cellular photodamage can occur and may initiate photocarcinogenesis [44][45][46] .…”

Suppression of UVB-induced phosphorylation of mitogen-activated protein kinases and nuclear factor kappa B by green tea polyphenol in SKH-1 hairless mice

“…JNK pathways are also involved in the phosphorylation and activation of several transcription factors, including c-Jun (Derijard et al, 1994), ATF-2 (Read et al, 1997), Elk-1 (Cavigelli et al, 1995), and p53 (Milne et al, 1995). Studies have demonstrated that cell exposure to UV irradiation causes activation of the MAPK pathway (Chen et al, 2002;Chouinard et al, 2002;Iordanov et al, 2002;She et al, 2002). JNK1/2 and p38 kinases are potently activated by various forms of stress, such as UV, heat shock, and inflammation Figure 7 Inhibitory effect of green tea polyphenol on UVBinduced activation of IKKa, and phosphorylation and degradation of IkBa in SKH-1 hairless mice.…”

“…of 12 mice (*Po0.001 vs UVB). ns, nonspecific Suppression of UVB effects in mouse skin by GTP F Afaq et al (Derijard et al, 1994;Chen et al, 2002;Chouinard et al, 2002;Iordanov et al, 2002). Experimental studies have shown that ERK1/2 and p38 are involved in the transcriptional activation of NF-kB (Adderley and Fitzgerald, 1999;Carter et al, 1999).…”