The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun.
The involvement of p38 in fundamental physiological processes and the fact that deregulation often leads to disease indicates the potential impact of p38 dependent mechanisms. Here we demonstrate a new pathway that includes the induction of the mitogen activated protein kinase p38 by protein kinase C and results in a specific phosphorylation of c-Jun in T-lymphocytes. P38 directly phosphorylates c-Jun within its transactivation domain at serine 63 and serine 73 and thus posttranscriptionally affects the presence of DNA-bound phosphorylated c-Jun, a prerequisite for activator protein 1 dependent gene transcription. Moreover, DNA-binding activity of c-Fos, FosB, and JunB were also dependent on the p38 protein kinase activity, whereas JunD, Fra-1 and Fra-2 were not affected. Although we show that stress induced mitogen activated protein kinases share c-Jun as a substrate for phosphorylation, p38 mediated effects could not be rescued by the c-Jun N-terminal kinases. This demonstrates that the protein kinase p38 plays a unique and non-redundant role in posttranslational c-Jun regulation. The induction of a p38 dependent c-Jun phosphorylation was comparable in both CD4(+) and CD8(+) T-cells, proposing a ubiquitous pathway that is not linked to T-cell subtype and effector function. In contrast, ATF-2 was predominantly phosphorylated in CD8(+) T-cells. Different cell lines show p38-dependent c-Jun phosphorylation upon phorbol ester induction but there is evidence that the simian virus 40 large T-antigen may interfere with this pathway.
Humar
Matjaz
M
Center for Clinical Research, Department of Anesthesiology, University Hospital Freiburg, Breisacherstrasse 66, D-79106 Freiburg, Germany. humar@ana1.ukl.uni-freiburg.de
Loop
Torsten
T
Schmidt
Rene
R
Hoetzel
Alexander
A
Roesslein
Martin
M
Andriopoulos
Nikolaos
N
Pahl
Heike L
HL
Geiger
Klaus K
KK
Pannen
Benedikt H J
BH
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D003609:Dactinomycin; D012694:Serine; C016658:phorbolol myristate acetate; D004247:DNA; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate