PKC-? mediates interferon-?-induced apoptosis through c-Jun NH?-terminal kinase activation.

ABSTRACT: BACKGROUND: Interferon-? (IFN-?) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-? induced a sustained activation of c-Jun NH?-terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-?-initiated activation of JNK1. RESULTS: IFN-? caused activation of PKC-? in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-?. The dominant-negative form of mutant PKC-? (dnPKC-?) reduced the IFN-?-induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (??m), and increase in propidium iodide (PI) positive cells. The IFN-?-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-? inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-? enhanced the IFN-?-induced TRAIL promoter activity and loss of ??m in Daudi B lymphoma cells. In addition, IFN-?-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-?. CONCLUSIONS: IFN-? induced JNK1 activation via PKC-?, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of ??m and increase in PI positive cells. The IFN-?-induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC-?-mediated signaling component(s).

SUBMITTER: Yanase N 

PROVIDER: S-EPMC3353249 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature