Phorbol ester-dependent activation of peroxiredoxin I gene expression via a protein kinase C, Ras, p38 mitogen-activated protein kinase signaling pathway.
The antioxidant protein peroxiredoxin (Prx) I is a thioredoxin peroxidase that is involved in the regulation of proliferation and differentiation of mammalian cells. Here, it is shown that Prx I gene expression was induced transcriptionally by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in cultured rat liver tissue macrophages and RAW264.7 monocytic cells. TPA-dependent induction of Prx I gene expression was mediated by two proximal activator protein-1 sites of the rat Prx I promoter region that were nuclear targets of c-Jun as determined by transfection studies with luciferase reporter gene constructs and electrophoretic mobility shift assays. The transcription factor Nrf2, however, was not involved in the regulation of Prx I promoter activity. Prx I gene induction by TPA was decreased by protein kinase C inhibitors and overexpressed dominant negative forms of Ras and MEKK1, but not Raf-1. The p38 MAPK inhibitor SB202190 and overexpression of dominant negative mutants of MAPK kinase 4 (MKK4), MKK6, and p38 inhibited the TPA-dependent induction of Prx I gene transcription. In contrast, inhibitors of the JNK, SP600125, and the NF-kappaB signaling pathway, caffeic acid phenethyl ester, respectively, as well as overexpressed dominant negative MKK7 and IkappaB, had no effect on the up-regulation of Prx I reporter gene activity by TPA. Cotransfection of wild-type p38alpha and p38beta, but not that of p38gamma and p38delta, increased Prx I promoter activity. The data indicate that a protein kinase C, Ras, MEKK1, p38 MAPK signaling pathway plays a major role for the transcriptional up-regulation of Prx I gene expression.
Hess
Alexander
A
Institut für Klinische Chemie und Pathobiochemie, Justus-Liebig-Universität Giessen, Giessen D-35392, Germany.
Wijayanti
Nastiti
N
Neuschäfer-Rube
Andrea Pathe
AP
Katz
Norbert
N
Kietzmann
Thomas
T
Immenschuh
Stephan
S
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D002273:Carcinogens; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010544:Peroxidases / Q000096:biosynthesis* / Q000235:genetics*; D054464:Peroxiredoxins; D010703:Phorbol Esters / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D002273:Carcinogens; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D010703:Phorbol Esters; D020033:Protein Isoforms; D010544:Peroxidases; D054464:Peroxiredoxins; D008156:Luciferases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate