Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2013-12-20

AUTHORS

Peter E. Czabotar, Guillaume Lessene, Andreas Strasser, Jerry M. Adams

ABSTRACT

Key PointsThe BCL-2 protein family principally determines whether a cell commits to apoptosis and hence has crucial roles in development, tissue homeostasis and immunity. Consequently, alteration of this control can either promote cancer and autoimmune diseases (too little apoptosis) or augment ischaemic conditions and contribute to degenerative disorders (too much apoptosis).The life-or-death decision for a cell is mainly determined by the interactions between three factions of the BCL-2 family: namely, the pro-survival subfamily (for example, BCL-2, BCL-XL and MCL1) and two pro-apoptotic factions, the BH3-only proteins (for example, BIM, PUMA and BID), which convey various cytotoxic signals, and the death effectors BAX and BAK, which can convert into homo-oligomers that perforate the mitochondrial outer membrane, triggering the proteolytic cascade that demolishes the cell.Biochemical and structural studies have shown that the cardinal interaction within the family is the engagement of a groove on the surface of the pro-survival family members, and of BAX and BAK, by the BH3 domain of a pro-apoptotic family member.Insights have recently emerged into how BAX and BAK convert from inert globular monomers into the lethal oligomers that permeabilize the mitochondrial outer membrane. They can be activated by the binding of certain BH3 domains (particularly those of BIM and BID) to their canonical surface groove, and possibly also to a less defined rear site on BAX. The groove binding provokes BAX and BAK to undergo remarkable structural rearrangements that include release of their own BH3 domain, which can then engage the surface groove of another BAX or BAK molecule to form the 'symmetric dimers' that nucleate the larger oligomers.Collectively, the manipulation of BCL-2 family genes in mice indicates that all mammalian cells are poised to commit suicide unless protected by one or more of the pro-survival family members; that nearly all cytotoxic signals, including those used in chemotherapy, are mediated through the activation of one or more BH3-only proteins; and that the activation of either BAX or BAK is necessary and sufficient for mitochondrial pathway apoptosis.Novel anticancer drugs, termed 'BH3 mimetics', which engage the groove of certain pro-survival family members in a manner that is similar to that of the BH3-only proteins, have shown promise in preclinical studies and early clinical trials, particularly in patients with lymphoid malignancies, such as chronic lymphocytic leukaemia. The best characterized are navitoclax (ABT-263), which targets BCL-2, BCL-XL and BCL-W, and the new BCL-2-specific ABT-199. Their combination with other anticancer agents is likely to extend their efficacy to a wider range of malignancies. More... »

PAGES

49-63

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  • Journal

    TITLE

    Nature Reviews Molecular Cell Biology

    ISSUE

    1

    VOLUME

    15

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrm3722

    DOI

    http://dx.doi.org/10.1038/nrm3722

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1001448882

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24355989


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