Abstract
Ultraviolet light A (UVA) plays an important role in the etiology of human skin cancer, and UVA-induced signal transduction has a critical role in UVA-induced skin carcinogenesis. The upstream signaling pathways leading to p70(S6K) phosphorylation and activation are not well understood. Here, we observed that UVA induces phosphorylation and activation of p70(S6K). Further, UVA-stimulated p70(S6K) activity and phosphorylation at Thr(389) were blocked by wortmannin, rapamycin, PD98059, SB202190, and dominant negative mutants of phosphatidylinositol (PI) 3-kinase p85 subunit (DNM-Deltap85), ERK2 (DNM-ERK2), p38 kinase (DNM-p38), and JNK1 (DNM-JNK1) and were absent in Jnk1-/- or Jnk2-/- knockout cells. The p70(S6K) phosphorylation at Ser(411) and Thr(421)/Ser(424) was inhibited by rapamycin, PD98059, or DNM-ERK2 but not by wortmannin, SB202190, DNM-Deltap85, or DNM-p38. However, Ser(411), but not Thr(421)/Ser(424) phosphorylation, was suppressed in DNM-JNK1 and abrogated in Jnk1-/- or Jnk2-/- cells. In vitro assays indicated that Ser(411) on immunoprecipitated p70(S6K) proteins is phosphorylated by active JNKs and ERKs, but not p38 kinase, and Thr(421)/Ser(424) is phosphorylated by ERK1, but not ERK2, JNKs, or p38 kinase. Moreover, p70(S6K) co-immunoprecipitated with PI 3-kinase and possibly PDK1. The complex possibly possessed a partial basal level of phosphorylation, but not at MAPK sites, which was available for its activation by MAPKs in vitro. Thus, these results suggest that activation of MAPKs, like PI 3-kinase/mTOR, may be involved in UVA-induced phosphorylation and activation of p70(S6K).
Highlights
Ultraviolet light A (UVA)1 (320 – 400 nm) comprises ϳ95% of the total solar UV reached the earth [1], because all the ultra
UVA-stimulated p70S6K activity and phosphorylation at Thr389 were blocked by wortmannin, rapamycin, PD98059, SB202190, and dominant negative mutants of phosphatidylinositol (PI) 3-kinase p85 subunit (DNM⌬p85), ERK2 (DNM-ERK2), p38 kinase (DNM-p38), and JNK1 (DNM-JNK1) and were absent in Jnk1؊/؊ or Jnk2؊/؊ knockout cells
Our data showed that UVA-induced phosphorylation of p70S6K at Thr389 was completely abrogated by pretreatment with rapamycin (Fig. 4A), a selective mammalian target of rapamycin (mTOR) inhibitor that abolishes mTOR function both in vivo and in vitro [12, 53]
Summary
Ultraviolet light A (UVA)1 (320 – 400 nm) comprises ϳ95% of the total solar UV reached the earth [1], because all the ultra-. Our data showed that UVA-induced phosphorylation of p70S6K at Thr389, but not at Ser411 or Thr421/Ser424, was inhibited by pretreatment of JB6 cells with wortmannin (Fig. 3A), a selective inhibitor of the PI 3-kinase p110 subunit [51].
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