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      MOMP, cell suicide as a BCL-2 family business

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      Author(s): 1 , 1 , *
      Publication date (Electronic):
      Journal: Cell Death and Differentiation
      Publisher: Nature Publishing Group

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          Abstract

          Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit.

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          Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.

          P. Li, D Nijhawan, I Budihardjo … (1997)
          We report here the purification of the third protein factor, Apaf-3, that participates in caspase-3 activation in vitro. Apaf-3 was identified as a member of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. Activated caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from S-100 extracts diminished caspase-3 activation. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
          Article 0 comments Cited 555 times – based on 0 reviews     Review now
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            Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.

            Lin Chen, Simon N. Willis, Andrew Wei … (2005)
            Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. Strikingly, Noxa bound only Mcl-1 and A1. In accord with their complementary binding, Bad and Noxa cooperated to induce potent killing. The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
            Article 0 comments Cited 460 times – based on 0 reviews     Review now
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              Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

              L Galluzzi, J M Bravo-San Pedro, I Vitale … (2014)
              Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Death Differ
                Journal ID (iso-abbrev): Cell Death Differ
                Title: Cell Death and Differentiation
                Publisher: Nature Publishing Group
                ISSN (Print): 1350-9047
                ISSN (Electronic): 1476-5403
                Publication date (Print): January 2018
                Publication date (Electronic): 20 October 2017
                Publication date PMC-release: 1 January 2018
                Volume: 25
                Issue: 1
                Pages: 46-55
                Affiliations
                [1 ]Department of Immunology, St. Jude Children’s Research Hospital , 262 Danny Thomas Place, Memphis, TN 38105, USA
                Author notes
                [* ]Department of Immunology, St. Jude Children's Research Hospital , MS 351, Room E7050, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA. Tel: +1 901 595 3470; Fax: +1 901 595 3107. E-mail: douglas.green@ 123456stjude.org
                Article
                Publisher Item ID: cdd2017179
                DOI: 10.1038/cdd.2017.179
                PMC ID: 5729535
                PubMed ID: 29053143
                SO-VID: 3cbbb087-5c4d-49df-bb91-e5c1ec00350f
                Copyright © Copyright © 2018 The Author(s)
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 27 July 2017
                Date revision received : 13 September 2017
                Date accepted : 18 September 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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