The BCL-2 family reunion.

B cell CLL/lymphoma-2 (BCL-2) and its relatives comprise the BCL-2 family of proteins, which were originally characterized with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis. Current observations expand BCL-2 family function to include numerous cellular pathways. Here we will discuss the mechanisms and functions of the BCL-2 family in the context of these pathways, highlighting the complex integration and regulation of the BCL-2 family in cell fate decisions.

[1]  D. Green,et al.  A Matter of Life and Death , 2008, Science.

[2]  Xu Luo,et al.  A three-helix homo-oligomerization domain containing BH3 and BH1 is responsible for the apoptotic activity of Bax. , 2007, Genes & development.

[3]  C. Scott,et al.  The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. , 2006, Cancer cell.

[4]  R. Youle,et al.  Role of Bax and Bak in mitochondrial morphogenesis , 2006, Nature.

[5]  David L. Vaux,et al.  Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells , 1988, Nature.

[6]  Sara Cipolat,et al.  OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion , 2006, Cell.

[7]  P. Sorger,et al.  Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis , 2009, Nature.

[8]  N D Marchenko,et al.  Death Signal-induced Localization of p53 Protein to Mitochondria , 2000, The Journal of Biological Chemistry.

[9]  G. Salvesen,et al.  The apoptosome: signalling platform of cell death , 2007, Nature Reviews Molecular Cell Biology.

[10]  David W. Andrews,et al.  Embedded together: The life and death consequences of interaction of the Bcl-2 family with membranes , 2007, Apoptosis.

[11]  G. Semenza,et al.  Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia* , 2008, Journal of Biological Chemistry.

[12]  Luca Scorrano,et al.  A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. , 2002, Developmental cell.

[13]  Mason R. Mackey,et al.  Bid, Bax, and Lipids Cooperate to Form Supramolecular Openings in the Outer Mitochondrial Membrane , 2002, Cell.

[14]  C. Day,et al.  Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. , 2009, Molecular cell.

[15]  Satoshi O. Suzuki,et al.  Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice , 2009, Nature Cell Biology.

[16]  H. Pehamberger,et al.  Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  A. Petros,et al.  Structural biology of the Bcl-2 family of proteins. , 2004, Biochimica et biophysica acta.

[18]  Osamu Takeuchi,et al.  Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. , 2009, Molecular cell.

[19]  R. Youle,et al.  Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. , 2004, Molecular biology of the cell.

[20]  S. Armstrong,et al.  Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. , 2006, Cancer cell.

[21]  M. Eisenstein,et al.  Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL , 2009, Autophagy.

[22]  F. Bazan,et al.  Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival , 2010, Nature.

[23]  A. Strasser,et al.  Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2 , 1990, Nature.

[24]  Colin Adrain,et al.  Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. , 2006, Molecular cell.

[25]  J. Hsieh,et al.  Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies , 2006, Nature Cell Biology.

[26]  M. Bootman,et al.  The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor , 2009, Proceedings of the National Academy of Sciences.

[27]  B. Mollereau.  Cell death: what can we learn from flies? Editorial for the special review issue on Drosophila apoptosis , 2009, Apoptosis.

[28]  Roland L. Dunbrack,et al.  Oligomerization of BAK by p53 Utilizes Conserved Residues of the p53 DNA Binding Domain* , 2008, Journal of Biological Chemistry.

[29]  Jing Wang,et al.  Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes , 2008, Nature Immunology.

[30]  J. Vicencio,et al.  BH3-Only Proteins and BH3 Mimetics Induce Autophagy by Competitively Disrupting the Interaction between Beclin 1 and Bcl-2/Bcl-XL , 2007, Autophagy.

[31]  D. Green,et al.  How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? , 2008, Trends in cell biology.

[32]  Guido Kroemer,et al.  Autophagy in the Pathogenesis of Disease , 2008, Cell.

[33]  S. Frank,et al.  The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. , 2001, Developmental cell.

[34]  S. Pattingre,et al.  JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. , 2008, Molecular cell.

[35]  Michael T. Certo,et al.  Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. , 2007, The Journal of clinical investigation.

[36]  R. D'Hooge,et al.  Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling , 2006, Cell.

[37]  J. Martinou,et al.  Inhibiting the Mitochondrial Fission Machinery Does Not Prevent Bax/Bak-Dependent Apoptosis , 2006, Molecular and Cellular Biology.

[38]  C. Mannella,et al.  Structural and functional features and significance of the physical linkage between ER and mitochondria , 2006, The Journal of cell biology.

[39]  Michael O. Hengartner,et al.  Developmental cell biology: Developmental apoptosis in C. elegans: a complex CEDnario , 2006, Nature Reviews Molecular Cell Biology.

[40]  L. Scorrano,et al.  Mitofusin 2 tethers endoplasmic reticulum to mitochondria , 2008, Nature.

[41]  D. Andrews,et al.  Membrane Binding by tBid Initiates an Ordered Series of Events Culminating in Membrane Permeabilization by Bax , 2008, Cell.

[42]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1α , 2006, Science.

[43]  Y. Hsu,et al.  Nonionic Detergents Induce Dimerization among Members of the Bcl-2 Family* , 1997, The Journal of Biological Chemistry.

[44]  J. Martinou,et al.  hFis1, a Novel Component of the Mammalian Mitochondrial Fission Machinery* , 2003, Journal of Biological Chemistry.

[45]  T. Kuwana,et al.  Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins , 2008, Proceedings of the National Academy of Sciences.

[46]  J. Opferman,et al.  NIX is required for programmed mitochondrial clearance during reticulocyte maturation , 2007, Proceedings of the National Academy of Sciences.

[47]  S. Korsmeyer,et al.  Obligate Role of Anti-Apoptotic MCL-1 in the Survival of Hematopoietic Stem Cells , 2005, Science.

[48]  C. Reynolds,et al.  Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy , 2009, Clinical Cancer Research.

[49]  Nektarios Tavernarakis,et al.  Functional and physical interaction between Bcl‐XL and a BH3‐like domain in Beclin‐1 , 2007, The EMBO journal.

[50]  P. Colman,et al.  To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. , 2008, Molecular cell.

[51]  Patrick Dumont,et al.  Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex , 2004, Nature Cell Biology.

[52]  K. Vousden,et al.  PUMA and Bax-induced Autophagy Contributes to Apoptosis , 2009, Cell Death and Differentiation.

[53]  C. Blackstone,et al.  Release of OPA1 during Apoptosis Participates in the Rapid and Complete Release of Cytochrome c and Subsequent Mitochondrial Fragmentation* , 2005, Journal of Biological Chemistry.

[54]  Mari Nishino,et al.  Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Yigong Shi,et al.  Crystal Structure of the Bcl-XL-Beclin 1 Peptide Complex , 2007, Journal of Biological Chemistry.

[56]  J Salvage,et al.  A matter of life and death. , 1981, Nursing times.

[57]  Tullio Pozzan,et al.  BAX and BAK Regulation of Endoplasmic Reticulum Ca2+: A Control Point for Apoptosis , 2003, Science.

[58]  Martin Schuler,et al.  Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis , 2004, Science.

[59]  Mark H Ellisman,et al.  Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. , 2008, Molecular cell.

[60]  Craig Brooks,et al.  Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins , 2007, Proceedings of the National Academy of Sciences.

[61]  A. M. van der Bliek,et al.  The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. , 2008, Molecular biology of the cell.

[62]  T. Kuwana,et al.  PUMA Couples the Nuclear and Cytoplasmic Proapoptotic Function of p53 , 2005, Science.

[63]  W. D. Fairlie,et al.  Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands , 2008, Cell Death and Differentiation.

[64]  S. Korsmeyer,et al.  bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation , 1989, Cell.

[65]  A. Winoto,et al.  During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain , 2008, The Journal of experimental medicine.

[66]  Seamus J. Martin,et al.  Emerging role for members of the Bcl-2 family in mitochondrial morphogenesis. , 2009, Molecular cell.

[67]  James E. Goldman,et al.  Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel Bcl-2-Interacting Protein , 1998, Journal of Virology.

[68]  Erinna F. Lee,et al.  The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins , 2009, The Journal of cell biology.

[69]  S. Korsmeyer,et al.  An inhibitor of Bcl-2 family proteins induces regression of solid tumours , 2005, Nature.

[70]  Petr Pancoska,et al.  p53 has a direct apoptogenic role at the mitochondria. , 2003, Molecular cell.

[71]  A. Letai,et al.  Diagnosing and exploiting cancer's addiction to blocks in apoptosis , 2008, Nature Reviews Cancer.

[72]  S. Cullen,et al.  Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release. , 2008, Molecular cell.

[73]  J. Estaquier,et al.  Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis , 2007, Cell Death and Differentiation.

[74]  N. Tjandra,et al.  BAX Activation is Initiated at a Novel Interaction Site , 2008, Nature.

[75]  Mark H. Ellisman,et al.  Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis , 2007, Nature Cell Biology.

[76]  Peter Walter,et al.  Supporting Online Material for An ER-Mitochondria Tethering Complex Revealed by a Synthetic Biology Screen , 2009 .

[77]  Liat Mizrachy,et al.  Differential Interactions Between Beclin 1 and Bcl-2 Family Members , 2007, Autophagy.

[78]  T. Kuwana,et al.  BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. , 2005, Molecular cell.

[79]  Brian J. Smith,et al.  Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. , 2005, Molecular cell.

[80]  Rachel T. Uren,et al.  Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak , 2007, The Journal of cell biology.

[81]  C. Thompson,et al.  Interleukin-3 Withdrawal Induces an Early Increase in Mitochondrial Membrane Potential Unrelated to the Bcl-2 Family , 2001, The Journal of Biological Chemistry.

[82]  S. Frank,et al.  Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis , 2002, Journal of Cell Biology.

[83]  T. Kuwana,et al.  Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. , 2008, Developmental cell.

[84]  Erinna F. Lee,et al.  Apoptosis Initiated When BH3 Ligands Engage Multiple Bcl-2 Homologs, Not Bax or Bak , 2007, Science.

[85]  S. Pattingre,et al.  Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy* , 2009, Journal of Biological Chemistry.

[86]  H. Sandoval,et al.  Essential role for Nix in autophagic maturation of erythroid cells , 2008, Nature.

[87]  T. Kuwana,et al.  The multidomain proapoptotic molecules Bax and Bak are directly activated by heat. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[88]  N. Fu,et al.  Baxbeta: a constitutively active human Bax isoform that is under tight regulatory control by the proteasomal degradation mechanism. , 2009, Molecular cell.

[89]  S. Korsmeyer,et al.  Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. , 2002, Cancer cell.

[90]  V. Mootha,et al.  tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. , 2000, Genes & development.