Figure 3. UVR-induced reactive oxygen species activate p38- and JNK-dependent signaling.

UVR-induced activation of p38 and JNK in keratinocytes can elicit both pro- and anti-survival mechanisms. (A.) In the presence of ROS, ASK1 is activated by dissociation from Trx1. ASK1 phosphorylates MKK 3 and 6, which activate p38 by phosphorylation at Thr¹⁸⁰ and Tyr¹⁸². ROS production also inhibits MKPs, which results in increased p38 activation. Once activated, p38 can act on multiple targets. It can promote apoptosis by phosphorylating p53 at Ser³³ and Ser⁴⁶ or induce NOXA-dependent apoptosis through increased protein expression of HIF-1α. Conversely, p38 can increase cell survival by upregulating Bcl-XL and COX-2 or direct phosphorylation of GSK3β at Thr⁴³ and Thr ³⁹⁰. (B.) Analogous to p38, after phosphorylation by ASK1, MKK4 and 7 activate JNK by phosphorylating Thr¹⁸³ and Tyr¹⁸⁵. Reduced MKP activity can also activate JNK. JNK targets include the AP1 transcription factor, which stimulates cell proliferation in the presence of UVB as a result of JNK phosphorylation of c-Jun at Ser⁶³ and Ser⁷³. Conversely, JNK can respond to excessive damage by activating apoptosis. High dose UVB can induce JNK-dependent nuclear localization of the pro-apoptotic factor FOXO3a, and JNK can inhibit the pro-survival Bcl-2 either directly or indirectly though activation of BIM.