Protein kinase C theta and epsilon promote T-cell survival by a rsk-dependent phosphorylation and inactivation of BAD.
Both MAPK and protein kinase C (PKC) signaling pathways promote cell survival and protect against cell death. Here, we show that 12-O-tetradecanoylphorbol-13-acetate (TPA) prevents Fas-induced apoptosis in T lymphocytes. The effect of TPA was specifically abolished by the PKC inhibitor GF109203X and by dominant negative PKCtheta, PKCepsilon, and PKCalpha, suggesting that novel and conventional PKC isoforms mediate phorbol ester action. Moreover, TPA stimulated phosphorylation of BAD at serine 112, an effect abrogated by GF109203X but not by the MEK inhibitor PD98059. Expression of constitutively active PKC increased the phosphorylation of BAD at serine 112 but not at serine 136. Additionally, Fas-mediated cell death was enhanced by overexpression of a catalytically inactive form of p90Rsk (Rsk2-KN). Finally, Rsk2-KN abolished the protective effect of constitutively active PKC and totally blocked phosphorylation of BAD on serine 112. Thus, novel PKCtheta and PKCepsilon rescue T lymphocytes from Fas-mediated apoptosis via a p90Rsk-dependent phosphorylation and inactivation of BAD.
Bertolotto
C
C
INSERM U526, Activation des Cellules Hématopoiétiques, Physiopathologie de la Survie et de la Mort Cellulaires et Infections Virales, Equipe Labelisée Ligue, 06107 Nice Cedex 2, France.
Maulon
L
L
Filippa
N
N
Baier
G
G
Auberger
P
P
D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D011494:Protein Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D002352:Carrier Proteins; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D051025:bcl-Associated Death Protein; D011494:Protein Kinases; C115197:calcium-independent protein kinase C; D019893:Ribosomal Protein S6 Kinases; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate