期刊
BIOCHEMICAL PHARMACOLOGY
卷 79, 期 12, 页码 1746-1758出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.02.010
关键词
Doxorubicin; Caspases; Bcl-2 family proteins; BH3-only proteins; AIF
资金
- Ministerio de Ciencia e Innovacion [5AF2007-60748, ISCIII-RTICC RD06/0020]
- Fundacion Mutua Madrilefia [PI080/08]
- Agence Nationale de la Recherche [ANR-09-BLAN-0247-01]
- Association pour la Recherche sur le Cancer [7987]
- Ramon y Cajal Program (Spanish Government)
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0247] Funding Source: Agence Nationale de la Recherche (ANR)
Bcl-2 family proteins are key regulators of the intrinsic apoptotic pathway, either facilitating (Bax, Bak, BH3-only) or inhibiting (Bcl-2, Bcl-x(L), Mcl-1, A1) mitochondrial release of apoptogenic factors. The role of caspases in this process is a matter of controversy. We have analyzed the relative contribution of caspases and Bcl-2 family of proteins in the induction phase of apoptosis triggered by doxorubicin in two p53-deficient leukemia cell lines, Jurkat and U937. First, we have found that caspases are dispensable for the induction phase of doxorubicin-induced apoptosis in both cell lines but they are needed to speed up the execution phase in Jurkat cells, not expressing Bax. Thus, down-regulation of Bak expression by siRNA significantly prevented doxorubicin-induced apoptosis in Jurkat but not in U937 cells. Reduction of Mcl-1 protein levels with siRNA increased sensitivity to apoptosis in both cell lines. Moreover, our results indicate that the contribution of BH3-only proteins to apoptosis is cell line specific. In Jurkat cells simultaneous silencing of Bim and PUMA was necessary to reduce doxorubicin-induced apoptosis. In U937 cells silencing of Bim or Noxa reduced sensitivity to doxorubicin. Immunoprecipitation experiments discarded an interaction between Mcl-1 and Bak in both cell lines and underscored the role of Bim and PUMA as mediators of Bax/Bak activation. (C) 2010 Elsevier Inc. All rights reserved.
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