title: Cytokine-induced p38 activation feedback regulates the prolonged activation of AKT cell survival pathway initiated by reactive oxygen species in response to UV irradiation in human keratinocytes.
abstract: A previous study has shown that UV activates the PI3K/AKT cell survival pathway while inducing cell death in human skin in vivo and cultured human keratinocytes in vitro, and yet the upstream pathway leading to the activation of AKT has not been thoroughly investigated. In this study we found that UV-induced phosphorylation of p38 and AKT in a time-dependent manner. The phosphorylation of p38 started at 5 min post UV irradiation, peaked at about 30 min, and remained elevated up to 2 h. The phosphorylation of AKT started at 15 min post UV treatment, peaked at about 1 h, and remained elevated up to 2 h. We also found that H2O2 induced phosphorylation of p38 and AKT in a time- dependent manner. Pretreatment with NAC abolished UV-induced AKT phosphorylation, suggesting the involvement of reactive oxygen species in AKT activation. Interestingly, SB203085, a known p38 inhibitor, had partially inhibited UV-induced AKT phosphorylation. Further studies showed that cytokines such as TNF-alpha and IL-1beta induced AKT phosphorylation in a time-dependent manner. Pretreatment with SB203085 inhibited IL-1beta-induced p38 and AKT phosphorylation. Collectively, our data suggest that UV activation of PI 3-kinase/AKT pathway is initiated by ROS and prolonged by feedback activation of p38 induced by released cytokines in response to UV irradiation in cultured human keratinocytes.
authors.affiliation: Department of Biomedical Sciences, Tufts University School of Veterinary Medicine, North Grafton, MA 01536, USA.
authors.forename: Q S
authors.initials: QS
authors.lastname: Zhang
authors.forename: D A
authors.initials: DA
authors.lastname: Maddock
authors.forename: J P
authors.initials: JP
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Heo
authors.forename: C
authors.initials: C
authors.lastname: Chiu
authors.forename: D
authors.initials: D
authors.lastname: Lai
authors.forename: K
authors.initials: K
authors.lastname: Souza
authors.forename: S
authors.initials: S
authors.lastname: Mehta
authors.forename: Y S
authors.initials: YS
authors.lastname: Wan
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000528:radiation effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580