Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes.
The effects of p38 MAP kinase and ERK on UVB induced c-fos gene expression were studied in a human keratinocyte cell line, FL30. UVB significantly increased c-fos gene expression at both the transcriptional and protein levels. p38 and ERK were also significantly activated after UVB irradiation. Treating the cells with p38 inhibitor SB202190 inhibited p38 activation, but not ERK; treating the cells with MEK-1 inhibitor PD98059 inhibited ERK activation without suppressing p38 activation. The kinase activation was determined by Western blots using phospho-p38 or ERK antibodies, or an in vivo p38 activity assay. Further studies demonstrated that blocking p38 almost completely abrogated UVB induced c-fos gene transcription and c-Fos protein synthesis. Inhibiting ERK partially abrogated UVB induced c-fos transcriptional and protein levels. Suppression of both p38 and ERK not only completely blocked UVB induced c-fos expression, but also decreased c-fos gene basal expression. Our data indicated that p38 may play a more important role than ERK in UVB induced c-fos expression in human keratinocytes. Since c-fos expression may play an important role in UVB induced AP-1 activation, and AP-1 activation is known to play a role in tumor promotion, both p38 and ERK could be potential targets for chemoprevention of skin cancer.
Chen
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Department of Radiation Oncology, Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, Arizona, AZ 85724, USA.
Bowden
G T
GT
D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000528:radiation effects; D016762:Genes, fos / Q000528:radiation effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000528:radiation effects; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D011725:Pyridines / Q000494:pharmacology; D014158:Transcription, Genetic; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C482125:MAP2K1 protein, human; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one