期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 282, 期 41, 页码 29831-29846出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M706110200
关键词
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资金
- NCI NIH HHS [R01 CA69008, R01 CA069008] Funding Source: Medline
Previous studies have suggested that Mcl- 1, an antiapoptotic Bcl- 2 homolog that does not exhibit appreciable affinity for the caspase 8- generated C- terminal Bid fragment ( tBid), diminishes sensitivity to tumor necrosis factor- alpha related apoptosis- inducing ligand ( TRAIL). This study was performed to determine the mechanism by which Mcl- 1 confers TRAIL resistance and to evaluate methods for overcoming this resistance. Affinity purification/ immunoblotting assays using K562 human leukemia cells, which contain Mcl- 1 and Bcl- x(L) as the predominant antiapoptotic Bcl- 2 homologs, demonstrated that TRAIL treatment resulted in binding of tBid to Bcl- xL but not Mcl- 1. In contrast, TRAIL caused increased binding between Mcl- 1 and Bak that was diminished by treatment with the caspase 8 inhibitor N-( N-alpha- acetylisoleucylglutamylthreonyl) asparticacid( O- methylester)- fluoromethylketone ( IETD( OMe)- fmk) or the c- Jun N- terminal kinase inhibitor SP600125. In addition, TRAIL caused increased binding of Bim and Puma to Mcl- 1 that was inhibited by IETD( OMe)- fmk but not SP600125. Further experiments demonstrated that down- regulation of Mcl- 1 by short hairpin RNA or the kinase inhibitor sorafenib increased TRAIL- induced Bak activation and death ligand- induced apoptosis in a wide variety of neoplastic cell lines as well as clinical acute myelogenous leukemia specimens. Collectively, these observations not only suggest a model in which Mcl- 1 confers TRAIL resistance by serving as a buffer for Bak, Bim, and Puma, but also identify sorafenib as a potential modulator of TRAIL sensitivity.
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