Abstract
UVA exposure plays an important role in the etiology of skin cancer. The family of p90-kDa ribosomal S6 kinases (p90(RSK)/MAPKAP-K1) are activated via phosphorylation. In this study, results show that UVA-induced phosphorylation of p90(RSK) at Ser(381) through ERKs and JNKs, but not p38 kinase pathways. We provide evidence that UVA-induced p90(RSK) phosphorylation and kinase activity were time- and dose-dependent. Both PD98059 and a dominant negative mutant of ERK2 blocked ERKs and p90(RSK) Ser(381) phosphorylation, as well as p90(RSK) activity. A dominant negative mutant of p38 kinase blocked UVA-induced phosphorylation of p38 kinase, but had no effect on UVA-induced Ser(381) phosphorylation of p90(RSK) or kinase activity. UVA-induced p90(RSK) phosphorylation and kinase activity were markedly attenuated in JnK1(-/-) and JnK2(-/-) cells. A dominant negative mutant of JNK1 inhibited UVA-induced JNKs and p90(RSK) phosphorylation and kinase activity, but had no effect on ERKs phosphorylation. PD169316, a novel inhibitor of JNKs and p38 kinase, inhibited phosphorylation of p90(RSK), JNKs, and p38 kinase, but not ERKs. However, SB202190, a selective inhibitor of p38 kinase, had no effect on p90(RSK) or JNKs phosphorylation. Significantly, ERKs and JNKs, but not p38 kinase, immunoprecipitated with p90(RSK) when stimulated by UVA and p90(RSK) was a substrate for ERK2 and JNK2, but not p38 kinase. These data indicate clearly that p90(RSK) Ser(381) may be phosphorylated by activation of JNKs or ERKs, but not p38 kinase.
Highlights
The incidence of nonmelanoma and melanoma skin cancers has been increasing for several decades in most parts of the world [1,2,3], but mainly in populations of European origin [3, 4]
extracellular signal-regulated kinases (ERKs) and Jun NH2-terminal kinases (JNKs), but not p38 kinase, immunoprecipitated with p90RSK when stimulated by UVA and p90RSK was a substrate for ERK2 and JNK2, but not p38 kinase
Our results showed that UVA-induced phosphorylation of p90RSK at Ser381 (Fig. 7, A and D) and JNKs (Fig. 7B), as well as p90RSK S6 kinase activity (Fig. 7E), were inhibited in DNM-JNK1 cells, but inhibition of ERKs phosphorylation was not observed (Fig. 7C)
Summary
The incidence of nonmelanoma and melanoma skin cancers has been increasing for several decades in most parts of the world [1,2,3], but mainly in populations of European origin [3, 4]. Results show that UVA-induced phosphorylation of p90RSK at Ser381 through ERKs and JNKs, but not p38 kinase pathways. A dominant negative mutant of JNK1 inhibited UVA-induced JNKs and p90RSK phosphorylation and kinase activity, but had no effect on ERKs phosphorylation.
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