BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak.

By W. Zong, T. Lindsten, Andrea J. Ross, G. MacGregor, Craig B. Thompson. Genes & Development, 2001

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The BH3-only proteins Bim and Bad bind to the antiapoptotic Bcl-2 proteins and induce apoptosis in wild-type cells and cells from either bax(-/-) or bak(-/-) animals. In contrast, constitutively active forms of Bim and Bad failed to induce apoptosis in bax(-/-)bak(-/-) cells. Expression of Bax restored susceptibility of the cells to Bim and Bad. In addition, Bax but not Bim or Bad sensitized the bax(-/-)bak(-/-) cells to a wide variety of cell death stimuli including UV irradiation, chemotherapeutic agents, and ER stress. These results suggest that neither activation of BH3-only proteins nor suppression of pro-survival Bcl-2 proteins is sufficient to kill cells in the absence of both Bax and Bak. Furthermore, whereas mouse embryo fibroblasts (MEF) expressing only Bax or Bak displayed resistance to transformation, bax(-/-)bak(-/-) MEF were nearly as prone to oncogenic transformation as p53(-/-) MEF. Thus, the function of either Bax or Bak appears required to initiate most forms of apoptosis and to suppress oncogenic transformation.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/bf4ba76d28c9b26fa9f8d1171fa19d057a6ca415

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Citations in the corpus

Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. (2007, background): “To exert their prodeath function, they require an intact BH3 domain (5) as well as the presence of BAX or BAK (6, 7).”
Akt-Directed Glucose Metabolism Can Prevent Bax Conformation Change and Promote Growth Factor-Independent Survival (2003, background): “The death of cells withdrawn from extrinsic signals requires the actions of the proapoptotic molecules Bax or Bak (38, 60, 68).”
Apoptosis and Molecular Targeting Therapy in Cancer (2014, background): “The central role that Bax/Bak play in apoptosis is supported by evidence that BH3-only proteins fail to trigger apoptosis in Bax/Bak-deficient cells [31, 32].”
Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control (2012, background): “The proapoptotic members can be separated into 2 distinct subfamilies: the BH3-only proteins, which include BH3 interacting domain death agonist (BID), BCL2/adenovirus E1B 19-kDa proteininteracting protein 3 (BNIP3), Nip3-like protein X (NIX)/ BCL2/adenovirus E1B 19-kDa protein-interacting protein 3”
Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes (2004, methodology): “DKO MEFs were treated with 20 μM etoposide plus 10 μM 3-MA in the presence of 2 μM PI and observed from 12 hours to 48 hours under a phase-contrast (6) and fluorescence (7) microscope.”
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies (2006, neutral): “dtd" [ ]> Apoptosis, or programmed cell death, results from the activation of an evolutionarily conserved genetic pathwa”
Alkylating DNA damage stimulates a regulated form of necrotic cell death. (2004, methodology): “MEFs and BMK cells were cultured as described (Zong et al. 2001; Degenhardt et al. 2002a).”
Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. (2003, background): “The function of these proapoptotic proteins can be further divided into the BH3-only proteins including Bid, Bad, and Bim and their effectors Bak and Bax (Cheng et al. 2001; Wei et al. 2001; Zong et al. 2001).”
Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis (2003, background): “, 2000), whereas the bax / bak / cells are resistant to virtually all death stimuli in a prolonged manner (Lindsten et al., 2000; Cheng et al., 2001; Wei et al., 2001; Zong et al., 2001).”