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Signal transduction pathways involved in phosphorylation and activation of p70S6K following exposure to UVA irradiation.

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).

Pubmed ID: 11279232


  • Zhang Y
  • Dong Z
  • Nomura M
  • Zhong S
  • Chen N
  • Bode AM
  • Dong Z


The Journal of biological chemistry

Publication Data

June 15, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: CA77646
  • Agency: NCI NIH HHS, Id: CA81064

Mesh Terms

  • Androstadienes
  • Animals
  • Cell Line
  • Enzyme Activation
  • Enzyme Inhibitors
  • Fibroblasts
  • Flavonoids
  • Imidazoles
  • MAP Kinase Signaling System
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein Subunits
  • Pyridines
  • Ribosomal Protein S6 Kinases
  • Sirolimus
  • Transfection
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases