Levine B, Sinha S, Kroemer GBcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4(5): 600-606

Howard Hughes Medical Institute, Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA.
Autophagy (Impact Factor: 11.75). 07/2008; 4(5):600-6. DOI: 10.4161/auto.6260
Source: PubMed


The essential autophagy protein and haplo-insufficient tumor suppressor, Beclin 1, interacts with several cofactors (Ambra1, Bif-1, UVRAG) to activate the lipid kinase Vps34, thereby inducing autophagy. In normal conditions, Beclin 1 is bound to and inhibited by Bcl-2 or the Bcl-2 homolog Bcl-X(L). This interaction involves a Bcl-2 homology 3 (BH3) domain in Beclin 1 and the BH3 binding groove of Bcl-2/Bcl-X(L). Other proteins containing BH3 domains, called BH3-only proteins, can competitively disrupt the interaction between Beclin 1 and Bcl-2/Bcl-X(L) to induce autophagy. Nutrient starvation, which is a potent physiologic inducer of autophagy, can stimulate the dissociation of Beclin 1 from its inhibitors, either by activating BH3-only proteins (such as Bad) or by posttranslational modifications of Bcl-2 (such as phosphorylation) that may reduce its affinity for Beclin 1 and BH3-only proteins. Thus, anti-apoptotic Bcl-2 family members and pro-apoptotic BH3-only proteins may participate in the inhibition and induction of autophagy, respectively. This hitherto neglected crosstalk between the core machineries regulating autophagy and apoptosis may redefine the role of Bcl-2 family proteins in oncogenesis and tumor progression.


Available from: Guido Kroemer
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    • "Research works conducted on the study of the mechanism of autophagy in tumors has led to identifying the involvement of a family of proteins that are also involved in apoptosis mechanisms. This family of protein is called Bcl-2 and is localized on the outer mitochondrial membrane, already involved in the apoptotic mechanism (Levine et al., 2008). They are part of a family of more than 15 different proteins that are grouped into two categories according to which play a role in pro-apoptotic or antiapoptotic cells. "
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    • "Beclin-1, one of the key molecular players in autophagy, can also bind to Bcl-2 or another antiapoptotic molecule, Bcl-x L , owing to its BH3-like structure. Beclin-1 activates lipid kinase at the initial stages of autophagy [9] [10] when it "
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    • "In contrast, programmed cell death type I (apoptosis) and type II (autophagy) progress through special programs for cell death [4]. Depending on the cell type, there are correlations between apoptosis and autophagy, which are dependent and independent in distinct steps of their respective programs for cell death [5,6]. However, autophagy does not consume adenosine 5'-triphosphate (ATP) in the processing of cell death, as apoptosis does. "
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