QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.025452v1 70/3/1099    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Byun, H. S. Articles by Hur, G. M. Search for Related Content PubMed PubMed Citation Articles by Byun, H. S. Articles by Hur, G. M.

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

Department of Pharmacology (H.S.B., K.A.P., M.W., K.-J.Y., S.S., L.P., J.Y.K., J.P., J.H.S., G.M.H.), Cancer Research Institute (J.P., G.M.H.), College of Medicine, Chungnam National University, Daejeon, Korea; Glycomics Team, Division of Proteome Research, Korea Basic Science Institute, Daejeon, Korea (Z.-W.L.); and Cell and Cellular Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Z.-G.L.)

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-B 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.

Address correspondence to: Dr. Gang Min Hur, Department of Pharmacology, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea. E-mail: gmhur{at}cnu.ac.kr

This article has been cited by other articles:

				H.-M. Ni, X. Chen, W.-X. Ding, M. Schuchmann, and X.-M. Yin Differential Roles of JNK in ConA/GalN and ConA-Induced Liver Injury in Mice Am. J. Pathol., October 1, 2008; 173(4): 962 - 972. [Abstract] [Full Text] [PDF]