Bcl-2 Family Members: Dual Regulators of Apoptosis and Autophagy

Overview

Journal Autophagy

Specialty Cell Biology

Date 2008 May 24

PMID 18497563

Citations 364

Authors

Beth Levine

Sangita Sinha

Guido Kroemer

Affiliations

Soon will be listed here.

Abstract

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.

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References

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

Wei Y, Pattingre S, Sinha S, Bassik M, Levine B . JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008; 30(6):678-88. PMC: 2478643. DOI: 10.1016/j.molcel.2008.06.001. View

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A . Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003; 112(12):1809-20. PMC: 297002. DOI: 10.1172/JCI20039. View

Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S . Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007; 21(13):1621-35. PMC: 1899472. DOI: 10.1101/gad.1565707. View

Feng W, Huang S, Wu H, Zhang M . Molecular basis of Bcl-xL's target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J Mol Biol. 2007; 372(1):223-35. DOI: 10.1016/j.jmb.2007.06.069. View

Pattingre S, Levine B . Bcl-2 inhibition of autophagy: a new route to cancer?. Cancer Res. 2006; 66(6):2885-8. DOI: 10.1158/0008-5472.CAN-05-4412. View

Oberstein A, Jeffrey P, Shi Y . Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem. 2007; 282(17):13123-32. DOI: 10.1074/jbc.M700492200. View

Klionsky D . Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007; 8(11):931-7. DOI: 10.1038/nrm2245. View

Fimia G, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R . Ambra1 regulates autophagy and development of the nervous system. Nature. 2007; 447(7148):1121-5. DOI: 10.1038/nature05925. View

10.

Rodriguez-Enriquez S, Kim I, Currin R, Lemasters J . Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy. 2006; 2(1):39-46. PMC: 4007489. DOI: 10.4161/auto.2229. View

11.

Bassik M, Scorrano L, Oakes S, Pozzan T, Korsmeyer S . Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J. 2004; 23(5):1207-16. PMC: 380968. DOI: 10.1038/sj.emboj.7600104. View

12.

Liang C, E X, Jung J . Downregulation of autophagy by herpesvirus Bcl-2 homologs. Autophagy. 2007; 4(3):268-72. DOI: 10.4161/auto.5210. View

13.

Liang X, Kleeman L, Jiang H, Gordon G, Goldman J, Berry G . Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998; 72(11):8586-96. PMC: 110269. DOI: 10.1128/JVI.72.11.8586-8596.1998. View

14.

Kroemer G, Galluzzi L, Brenner C . Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87(1):99-163. DOI: 10.1152/physrev.00013.2006. View

15.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View

16.

Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S . Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy. 2007; 3(6):561-8. DOI: 10.4161/auto.4713. View

17.

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View

18.

Tasdemir E, Maiuri M, Tajeddine N, Vitale I, Criollo A, Vicencio J . Cell cycle-dependent induction of autophagy, mitophagy and reticulophagy. Cell Cycle. 2007; 6(18):2263-7. DOI: 10.4161/cc.6.18.4681. View

19.

Criollo A, Vicencio J, Tasdemir E, Maiuri M, Lavandero S, Kroemer G . The inositol trisphosphate receptor in the control of autophagy. Autophagy. 2007; 3(4):350-3. DOI: 10.4161/auto.4077. View

20.

Mathew R, Kongara S, Beaudoin B, Karp C, Bray K, Degenhardt K . Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007; 21(11):1367-81. PMC: 1877749. DOI: 10.1101/gad.1545107. View