Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ et al.. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 8: 1348-1358
Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Nature Cell Biology
(Impact Factor: 19.68).
01/2007; 8(12):1348-58. DOI: 10.1038/ncb1499
Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-X(L)-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-X(L) to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.
Available from: Gabriel Ichim
- "Proteins of both groups are regulated by a diverse group of proteins sharing only the BH3 domain with Bcl-2 proteins (BH3-only proteins). Pro-survival Bcl-2 proteins inhibit Bax and Bak via direct interactions or by sequestering 'activator' BH3-only proteins, thereby preventing their interaction with Bax and Bak (Letai et al, 2002; Kuwana et al, 2005; Willis et al, 2005, 2007; Kim et al, 2006; Llambi et al, 2011). Regulatory interactions between pro-and anti-apoptotic Bcl-2 proteins and Bax and Bak can only be observed in the presence of the OMM or liposomes and could result in membrane-integral protein complexes (Roucou et al, 2002), suggesting also mitochondrial apoptosis signaling via membrane-embedded proteins (Leber et al, 2007; Lovell et al, 2008; García-Sáez et al, 2009). "
[Show abstract] [Hide abstract]
ABSTRACT: The Bcl-2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro-survival Bcl-2 proteins control Bax by constant retrotranslocation into the cytosol of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this level of regulation. Here we report that Bak is retrotranslocated from the mitochondria by pro-survival Bcl-2 proteins. Bak is present in the cytosol of human cells and tissues, but low shuttling rates cause predominant mitochondrial Bak localization. Interchanging the membrane anchors of Bax and Bak reverses their subcellular localization compared to the wild-type proteins. Strikingly, the reduction of Bax shuttling to the level of Bak retrotranslocation results in full Bax toxicity even in absence of apoptosis induction. Thus, fast Bax retrotranslocation is required to protect cells from commitment to programmed death.
Available from: Kambiz Alavian
- "The Bcl-2 family also regulates outer membrane channel activity. During programmed cell death, mitochondrial outer membrane permeabilization (MOMP) (Green and Kroemer, 2004; Dejean et al., 2005; Adams and Cory, 2007), is produced by formation of large outer membrane pores comprised of activated oligomerized pro-apoptotic Bax proteins, aided by other pro-apoptotic moieties (Antonsson et al., 2000; Dejean et al., 2005; Kim et al., 2006). In their canonical role, the anti-apoptotic Bcl-2 family proteins such as Bcl-xL protect cells against MOMP by interacting with, and preventing the activities of, the pro-apoptotic family members (Galonek and Hardwick, 2006; Adams and Cory, 2007). "
[Show abstract] [Hide abstract]
ABSTRACT: Accepted features of neurodegenerative disease include mitochondrial and protein folding dysfunction and activation of pro-death factors. Neurons that experience high metabolic demand or those found in organisms with genetic mutations in proteins that control cell stress may be more susceptible to aging and neurodegenerative disease. In neurons, events that normally promote growth, synapse formation, and plasticity are also often deployed to control neurotoxicity. Such protective strategies are coordinated by master stress-fighting proteins. One such specialized protein is the anti-cell death Bcl-2 family member Bcl-xL, whose myriad death-protecting functions include enhancement of bioenergetic efficiency, prevention of mitochondrial permeability transition channel activity, protection from mitochondrial outer membrane permeabilization (MOMP) to pro-apoptotic factors, and improvement in the rate of vesicular trafficking. Synapse formation and normal neuronal activity provide protection from neuronal death. Therefore, Bcl-xL brings about synapse formation as a neuroprotective strategy. In this review we will consider how this multi-functional master regulator protein uses many strategies to enhance synaptic and neuronal function and thus counteracts neurodegenerative stimuli.
Available from: Mohamed Hassan
- "The former consists of Bax and Bak, which are essential for apoptosis . The BH3-only proteins are further divided into two subclasses: " activators " (e.g., Bim and tBid), which directly activate Bax/Bak to induce mitochondrial outer membrane permeabilization (MOMP), and " sensitizers/derepressors " (e.g., Bad, Bik, Bmf, Hrk, Noxa, and Puma), which do not activate Bax/Bak directly but instead neutralize antiapoptotic proteins  . The central role that Bax/Bak play in apoptosis is supported by evidence that BH3-only proteins fail to trigger apoptosis in Bax/Bak-deficient cells  . "
[Show abstract] [Hide abstract]
ABSTRACT: Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.