RT Journal Article
SR Electronic
T1 Phorbol 12-Myristate 13-Acetate Protects against Tumor Necrosis Factor (TNF)-Induced Necrotic Cell Death by Modulating the Recruitment of TNF Receptor 1-Associated Death Domain and Receptor-Interacting Protein into the TNF Receptor 1 Signaling Complex: Implication for the Regulatory Role of Protein Kinase C
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1099
OP 1108
DO 10.1124/mol.106.025452
VO 70
IS 3
A1 Hee Sun Byun
A1 Kyeong Ah Park
A1 Minho Won
A1 Keum-Jin Yang
A1 Sanghee Shin
A1 Longzhen Piao
A1 Jin Young Kwak
A1 Zee-Won Lee
A1 Jongsun Park
A1 Jeong Ho Seok
A1 Zheng-Gang Liu
A1 Gang Min Hur
YR 2006
UL http://molpharm.aspetjournals.org/content/70/3/1099.abstract
AB Protein kinase C (PKC) triggers cellular signals that regulate proliferation or death in a cell- and stimulus-specific manner. Although previous studies have demonstrated that activation of PKC with phorbol 12-myristate 13-acetate (PMA) protects cells from apoptosis induced by a number of mechanisms, including death receptor ligation, little is known about the effect or mechanism of PMA in the necrotic cell death. Here, we demonstrate that PMA-mediated activation of PKC protects against tumor necrosis factor (TNF)-induced necrosis by disrupting formation of the TNF receptor (TNFR)1 signaling complex. Pretreatment with PMA protected L929 cells from TNF-induced necrotic cell death in a PKC-dependent manner, but it did not protect against DNA-damaging agents, including doxorubicin (Adriamycin) and camptothecin. Analysis of the upstream signaling events affected by PMA revealed that it markedly inhibited the TNF-induced recruitment of TNFR1-associated death domain protein (TRADD) and receptor-interacting protein (RIP) to TNFR1, subsequently inhibiting TNF-induced activation of nuclear factor-κB and c-Jun NH2-terminal kinase (JNK). However, JNK inhibitors do not significantly affect TNF-induced necrosis, suggesting that the inhibition of JNK activation by PMA is not part of the antinecrotic mechanism. In addition, PMA acted as an antagonist of TNF-induced reactive oxygen species (ROS) production, thereby suppressing activation of ROS-mediated poly(ADP-ribose)polymerase (PARP), and thus inhibiting necrotic cell death. Furthermore, during TNF-induced necrosis, PARP was significantly activated in wild-type mouse embryonic fibroblast (MEF) cells but not in RIP-/- or TNFR-associated factor 2-/-MEF cells. Taken together, these results suggest that PKC activation ensures effective shutdown of the death receptor-mediated necrotic cell death pathway by modulating formation of the death receptor signaling complex. The American Society for Pharmacology and Experimental Therapeutics