title: The role of PI 3-kinase in the UVB-induced expression of c-fos.
abstract: The role of the PI 3-kinase signaling pathway in UVB-induced c-fos gene expression was investigated in a human keratinocyte cell line, HaCaT. The enzymatic activity of PI 3-kinase was increased threefold by 250 J/m(2) UVB. Inhibition of PI 3-kinase activity, via expression of a mutant p85 subunit or treatment with wortmannin, resulted in decreased levels of c-fos promoter activity and c-fos protein. Two members of the PI 3-kinase signaling pathway, Akt and GSK-3beta, were also found to affect c-fos transactivation. Expression of dominant negative Akt or wild-type GSK-3beta significantly inhibited UVB-induced c-fos promoter activity. In addition, when GSK-3beta activity was inhibited by lithium chloride, both c-fos promoter activity and protein levels increased. These results demonstrate that both Akt activation and GSK-3beta inactivation are required in the UVB-induction of c-fos. Our results demonstrate for the first time that UVB induction of c-fos is in part mediated by the PI 3-kinase signaling pathway in the HaCaT cell line. By identifying the multiple signaling pathways that are induced by UVB and contribute to the induction of c-fos expression, more drug targets may be identified to aid attempts to prevent and treat skin cancer.
authors.affiliation: Department of Molecular and Cellular Biology, Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, Arizona, AZ 85724, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gonzales
authors.forename: G Tim
authors.initials: GT
authors.lastname: Bowden
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers / Q000737:chemistry; D024202:Electrophoretic Mobility Shift Assay; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects*; D018021:Lithium Chloride / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014466:Ultraviolet Rays; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017931:DNA Primers; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D000077191:Wortmannin; C494918:AKT1 protein, human