RRC ID 1385
著者 Miyoshi N, Uchida K, Osawa T, Nakamura Y.
タイトル A link between benzyl isothiocyanate-induced cell cycle arrest and apoptosis: involvement of mitogen-activated protein kinases in the Bcl-2 phosphorylation.
ジャーナル Cancer Res
Abstract In the present study, we clarified the molecular mechanism underlying the relationship between benzyl isothiocyanate (BITC)-induced cell cycle arrest and apoptosis and the involvement of mitogen-activated protein kinases (MAPKs). The exposure of Jurkat human T-cell leukemia cells to BITC resulted in the inhibition of the G(2)-M progression that coincided with the apoptosis induction. The experiment using the phase-specific synchronized cells demonstrated that the G(2)-M phase-arrested cells are more sensitive to undergoing apoptotic stimulation by BITC than the cells in other phases. We also confirmed that BITC activated c-Jun N-terminal kinase (JNK) and p38 MAPK, but not extracellular signal-regulated kinase, at the concentration required for apoptosis induction. An experiment using a JNK-specific inhibitor SP600125 or a p38 MAPK inhibitor SB202190 indicated that BITC-induced apoptosis might be regulated by the activation of these two kinases. Conversely, BITC is likely to confine the Jurkat cells in the G(2)-M phase mainly through the p38 MAPK pathway because only the p38 MAPK inhibitor significantly attenuated the accumulation of inactive phosphorylated Cdc2 protein and the G(2)-M-arrested cell numbers. We reported here for the first time that the antiapoptotic Bcl-2 protein was phosphorylated by the BITC treatment without significant alteration of the Bcl-2 total protein amount. This was abrogated by a JNK specific inhibitor SP600125 at the concentration required for specific inhibition of the c-Jun phosphorylation. Moreover, the spontaneous phosphorylation of antiapoptotic Bcl-2 in the G(2)-M synchronized cells was enhanced synergistically by the BITC treatment. Involvement of the MAPK activation in the Bcl-2 phosphorylation and apoptosis induction also was observed in HL-60 and HeLa cells. Thus, we identified the phosphorylated Bcl-2 as a key molecule linking the p38 MAPK-dependent cell cycle arrest with the JNK activation by BITC.
巻・号 64(6)
ページ 2134-42
公開日 2004-3-15
DOI 10.1158/0008-5472.can-03-2296
PMID 15026354
MeSH Apoptosis / drug effects* CDC2 Protein Kinase / metabolism Cell Cycle / drug effects* Enzyme Inhibitors / pharmacology HL-60 Cells HeLa Cells Humans Isothiocyanates / pharmacology* JNK Mitogen-Activated Protein Kinases* Jurkat Cells MAP Kinase Kinase 4 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases / metabolism Mitogen-Activated Protein Kinases / metabolism* Phosphorylation / drug effects Proto-Oncogene Proteins c-bcl-2 / metabolism* Signal Transduction p38 Mitogen-Activated Protein Kinases
IF 9.727
引用数 115
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 Jurkat(RCB0806)