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Year : 2016  |  Volume : 2  |  Issue : 1  |  Page : 7-20

BCL2 Family, Mitochondrial Apoptosis, and Beyond

1 Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China
2 Division of Oncology Research, Mayo Clinic, Rochester, MN, USA

Date of Submission15-Nov-2015
Date of Acceptance24-Jan-2016
Date of Web Publication26-Feb-2016

Correspondence Address:
Haiming Dai
Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei 230031, Anhui
Scott H Kaufmann
Division of Oncology Research, Gonda 19-205, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905
X Wei Meng
Division of Oncology Research, Gonda 19-205, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2395-3977.177558

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Apoptosis is a morphologically and biochemically distinct form of cell death that plays an essential role in development, immune response, and tissue homeostasis. Diminished apoptosis is also considered a hallmark of cancer whereas many cancer treatments induce apoptosis in susceptible cells. Classically, this induction of apoptosis occurs through two major signaling pathways: the extrinsic pathway and the intrinsic pathway. It has been known for 20 years that B-cell lymphoma-2 (BCL2) family proteins control the intrinsic apoptotic pathway by regulating the process of mitochondrial outer membrane permeabilization (MOMP) through protein-protein interactions. Recent studies have elucidated how BCL2 antagonist/killer (BAK) and BCL2-associated X protein (BAX) are activated by BCL2 homology 3 (BH3)-only proteins and how activated BAK and BAX permeabilize MOM, providing increased understanding of how BCL2 family proteins control MOMP. Moreover, both structural and biochemical studies have revealed dual roles for anti-apoptotic BCL2 family proteins in inhibiting BH3-only proteins and restraining activated BAK and BAX. Here, we review recent advances in understanding how BCL2 family proteins control MOMP as well as new nonapoptotic functions for these proteins.

Keywords: Apoptosis, B-cell lymphoma-2 family, BAK/BAX activation, BH3 domain, mitochondrial outer membrane permeabilization

How to cite this article:
Dai H, Meng X W, Kaufmann SH. BCL2 Family, Mitochondrial Apoptosis, and Beyond . Cancer Transl Med 2016;2:7-20

How to cite this URL:
Dai H, Meng X W, Kaufmann SH. BCL2 Family, Mitochondrial Apoptosis, and Beyond . Cancer Transl Med [serial online] 2016 [cited 2021 Jan 17];2:7-20. Available from: http://www.cancertm.com/text.asp?2016/2/1/7/177558

  Introduction Top

Cell death plays an essential role in development, immune response, and tissue homeostasis. [1],[2] Apoptosis is a morphologically and biochemically distinct form of cell death that can be initiated by various stimuli. Morphologically, it is characterized by cell shrinkage followed by the formation of apoptotic bodies, membrane-enclosed cell fragments that are rapidly cleared by phagocytes after they recognize "eat-me" signals on the outer surface of the apoptotic cell's plasma membrane. [3]

During cancer development, apoptosis is often deregulated. In particular, anti-apoptotic proteins are often overexpressed during cancer formation. [4],[5],[6] Conversely, a large number of anti-cancer drugs can induce apoptosis in susceptible cells. [7],[8] Thus, apoptosis also plays an important role in cancer development and treatment.

Apoptosis can proceed through two different pathways [Figure 1]: the extrinsic pathway and the intrinsic pathway. [1],[2] The extrinsic pathway, also called the death receptor pathway, is initiated when certain members of the tumor necrosis factor super family bind to their cognate receptors, leading to the formation of an intracellular death-inducing signaling complex (DISC), DISC-mediated activation of a caspase cascade, and subsequent disassembly of the cell. [9],[10],[11] Death receptor-initiated apoptosis can either directly initiate the demise of some cells (type I cells, such as lymphocytes) or initiate cell death that requires BID-mediated activation of the intrinsic apoptosis pathway (type II cells, such as hepatocytes) due to lower expression levels of death receptors in these cells. [12]
Figure 1. Overview of apoptotic pathways: the death receptor and mitochondrial pathways. The death receptor pathway is initiated by members of tumor necrosis factor superfamily, which bind their receptors and cause activation of caspase 8. The mitochondrial pathway is controlled by the BCL2 protein family. Two members of this protein family, BAK and BAX, are directly responsible for breaching the mitochondrial outer membrane. Once this occurs, cytochrome C, Smac, and other mitochondria intermembrane proteins are released and facilitate the activation of downstream caspases, eventually leading to apoptosis. Cyto C: cytochrome c; BCL2: B cell lymphoma-2; BAK: B-cell lymphoma-2 antagonist/killer; BAX: B-cell lymphoma-2-associated X protein

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The intrinsic apoptotic pathway, also termed the mitochondrial pathway, is controlled by members of the B-cell lymphoma-2 (BCL2) protein family, which regulate mitochondrial outer membrane permeabilization (MOMP). Once MOMP occurs, mitochondrial intermembrane space proteins, including cytochrome c and Smac, are released. Cytosolic cytochrome c interacts with apoptotic protease activating factor 1 (Apaf-1) and procaspase-9 to form a complex called apoptosome, which facilitates caspase 9 activation. [13] Smac can bind and inactivate X-linked inhibitor of apoptosis (XIAP), which would otherwise inhibit caspase 9 activation. [3],[13],[14] Thus, MOMP initiates two processes that facilitate caspase activation.

  BCL2 Family Proteins Top

As indicated in [Figure 1], BCL2 family proteins play critical roles in the intrinsic apoptotic pathway. This family of proteins can be divided into three groups based on their structures and intracellular functions [Figure 2] and [Table 1]. One group includes BCL2 antogonist/killer (BAK) and BCL2-associated X protein (BAX), which are known as apoptosis effectors. Also called multidomain pro-apoptotic BCL2 family proteins, BAX and BAK contain BCL2 homology (BH) domains 1-3 and can directly permeabilize MOM when activated. Whether BCL2-related ovarian killer (BOK) belongs to this same subfamily is not clear. Structurally it is similar to BAK and BAX; [44] however, functionally it does not have the ability to permeabilize the MOM by itself but instead induces apoptosis only in the presence of BAK or BAX. [45]
Figure 2. Overview of the BCL2 protein family. The BCL2 protein family is divided into three groups such as multidomain pro-apoptotic BCL2 family proteins, BAK, and BAX; multi-domain anti-apoptotic BCL2 family proteins, including BCL2, BCLXL, BCLW, BCLB, MCL1 and A1; and BH3-only pro-apoptotic BCL2 family proteins, including BIM, PUMA, BID, BAD, NOXA, BIK, BMF, and HRK. The anti-apoptotic BCL2 family members generally have four BH domains. BAK and BAX have classically been thought to share BH 1-3 domains, although some studies have suggested that BAK and BAX also contain a BH4 domain as well BCL2: B-cell lymphoma-2; BAK: B-cell lymphoma-2 antagonist/killer; BAX: B-cell lymphoma-2-associated X protein; BCLXL: B-cell lymphoma-X large; MCL1: Myeloid cell leukemia 1; BH: B-cell lymphoma-2 homology

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Table 1: BCL2 family protein interactions and their regulation in cancer

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The second group, called anti-apoptotic or pro-survival BCL2 family members, includes BCL2, BCL-X large (BCLX L ), BCL2-like protein 2 (BCLW), BCL2-like protein 10 (BCLB), myeloid cell leukemia 1 (MCL1), and BCL2-related protein A1 (BFL1) (A1 in mouse). These proteins, which contain four BH domains (BH1-BH4), inhibit apoptosis by binding and sequestering their pro-apoptotic counterparts.

The final group, termed BH3-only proteins, includes BIM, PUMA, BID, BAD, NOXA, BIK, BMF, and HRK. These polypeptides share only a 15-25 residue BH3 domain in common with other BCL2 family proteins. This BH3 domain, however, is critical for the interactions of these proteins with other BCL2 family proteins to regulate MOMP.

BAK and BAX - effectors of mitochondrial permeabilization

Structure of BAK and BAX monomers

Structural studies have demonstrated that BAK and BAX monomers are globular structures consisting of a central hydrophobic core helix (α5) surrounded by eight alpha helices. [46],[47],[48] In the BAK monomer, four of these helices (α1, α3, α4, and α6) are long helices that form a circle around the central helix α5 while the others (α2, α7, and α8) are shorter and link either the longer helices or the main structure to the transmembrane (TM) domain which consists of helix α9. [46] The major structural difference between monomeric BAK and BAX is the orientation of helix α9. In BAX, this helix is buried in a hydrophobic groove formed by helices α3, α4, and α5. [48] In contrast, the hydrophobic groove of BAK is empty; and the α9 helix of BAK extends away from the remainder of the globular protein. Consequently, BAK is normally tethered to cytoplasmic surface of the MOM through this hydrophobic TM domain whereas BAX resides in cytosol. In addition, the hydrophobic groove of BAX must accommodate the α9 helix in the unactivated state. Therefore, the hydrophobic groove of BAX opens wider than that of BAK.

As a result of these differences in the structure of BAK and BAX monomers, the mechanisms of activation of these two proteins are thought to be different. [49],[50],[51],[52] Specifically, BAX activation is reportedly initiated through binding of activating ligands to the N-terminal domain containing the α1 and α2 helices. [49],[52] This results in a conformational change that releases α9 from the BAX hydrophobic BH3 binding groove and contributes to translocation of BAX from the cytoplasm to mitochondria. [49] Beyond this step, further activation occurs through the binding of activating ligands to the vacated BH3 binding groove. [50],[52] Recent structural studies have suggested that at least at some steps, specifically the binding of pro-apoptotic BH3-only family members to the BH3 binding groove followed by oligomerization are similar for BAK and BAX [44],[53] as described in greater detail below.

Models of BAK/BAX activation

Three different models have been proposed to explain BAK and BAX activation. One is the so-called direct activation model, in which certain BH3-only proteins are proposed to directly bind to BAK and/or BAX to induce their activation. [54],[56] According to this model, BH3-only proteins are divided into activators and sensitizers. [55],[56] Activators directly bind to BAK and/or BAX, causing a BAK/BAX conformational change that leads to the oligomerization of BAK/BAX and subsequent activation. In contrast, sensitizers bind anti-apoptotic BCL2 family proteins, releasing the BH3-only activators that are normally restrained by anti-apoptotic BCL2 proteins.

An alternative model, the indirect activation model (or displacement model), suggests that BAK and BAX are constitutively activated and are prevented from spontaneously inducing MOMP by their binding to anti-apoptotic BCL2 family proteins. According to this model, the role of BH3-only proteins is to neutralize the anti-apoptotic family members and release preactivated BAK and BAX. [57],[58]

More recently, a unified model has suggested that both direct activation and displacement models play roles in BAK/BAX activation, with anti-apoptotic BCL2 family members inhibiting MOMP by sequestering both direct activators and activated BAK and BAX. [59] This model has been supported by extensive studies. [60],[61],[62],[63],[64],[65]

Although BAX activation is reportedly initiated at the N-terminus, [49] a second step that involves binding of activators to the canonical BH3 binding groove is also required. [52] Different from BAX activation, BAK activation is initiated by BH3 domains binding exclusively at the canonical BH3 binding groove. [51] Biochemical studies have suggested that binding of activators to the canonical BH3 binding groove of BAK, which induces a conformational change in BAK BH3 domain, [51] might induce BAK octamerization. [66] Structural studies have confirmed that BAK activation is initiated at the canonical BH3 binding groove; [67] this model is also supported by a study using full-length BAK. [68]

Although BH3-only proteins are the major BAK/BAX activators, additional proteins also appear to be able to serve this function. In particular, p53, Casp8p41, and retinoblastoma protein have been reported to be direct activators. [69],[70],[71] Moreover, recent evidence suggests that activated BAK and BAX themselves might also serve as activators. [72],[73],[74]

BAK/BAX-mediated permeabilization of the mitochondrial outer membrane

When cells encounter conditions favoring apoptosis, BAK, and/or BAX are activated. Earlier studies have reported the exposure of cryptic N-terminal epitopes and transient exposure of BAK/BAX BH3 domains during the activation. [75],[76] After this BH3 domain exposure, BAK or BAX is thought to form a symmetric dimer through binding of the BH3 domain of one molecule to the canonical BH3 binding groove of its partner. This binding, which is similar to binding of a BH3 domain to anti-apoptotic BCL2 family proteins, is thought to be the basis for formation of higher order oligomers. [76],[77],[78] Oligomerization has been further found to involve the α6 helix of BAK or BAX. [79],[80] Structural studies have not only confirmed that symmetric dimers can form but also provided detailed information about the interaction interfaces in these dimers. [53],[67] Moreover, dissociation of the BAK α1 helix from the core domain before dimer formation is required for further activation. [81] However, the structure of higher order BAK/BAX oligomers remains unclear.

Another unresolved question is how activated BAK and BAX permeabilize the MOM. Structural studies have demonstrated that BAX [48] and BAK [46] share a similar fold with channel-forming domains of bacterial toxins such as diphtheria toxin [82] and colicin E1. [83] These toxins also contain 9–10 α helices and can permeabilize bacterial membranes, raising the possibility that BAX and BAK might use similar mechanisms to permeabilize the MOM. [84] Labeling with the cysteine-modifying chemical 4-acetamido-4'- ((iodoacetyl) amino) stilbene-2,2'- disulfonic acid (IASD) has been used to study how these toxins, [85] as well as BAX and BAK, permeabilize target membranes. [86] These assays defined residues along BAX helices α5, α6, and α9 that could not be labeled when BAX was activated, suggesting a "hairpin insertion model" for BAX when inserted into the MOM. [87] In addition, purified peptides derived from the pore-forming domain, which consists of the α5 and α6 helices of BAK or BAX, can independently form pores and permeabilize liposomes in vitro. [87],[88],[89] All of these observations suggest an important role for BAK/BAX helices α5 and α6 in permeabilizing the membrane. Moreover, electron paramagnetic resonance studies have suggested partial interaction of BAK α5 and α6 with liposomes. [90] In particular, the observation that only some of the residues in α5 and α6 of activated BAK and BAX could be labeled with IASD also agrees with a partial interaction model, suggesting an in-plane model in which α5 and α6 collapse onto the membrane to permeabilize the MOM. [91] However, this model does not agree with previous structural studies reporting that activated BAK and BAX must have their α5 and α6 helices separated when activated. [53],[67] Thus, the mechanisms by which BAK and BAX permeabilize the MOM require further investigation.

Nonapoptotic functions of BAK and BAX

Mitochondria are in a dynamic equilibrium between a fragmented state and a fused state. [92] BAK and BAX activation leads rapidly to mitochondrial fragmentation, [93],[94],[95] which occurs very close in time to MOMP and is associated with mitochondrial cytochrome c release. [96] However, constitutively fragmented mitochondria are also found in BAK(-/-)BAX(-/-) MEFs. [95] Furthermore, reexpression of BAK in these cells, under conditions where apoptosis does not occur, leads to increase in mitochondrial length, suggesting that BAX and/or BAK are required for mitochondrial fusion/elongation in the absence of apoptosis. [95] On the other hand, the large GTPase of the dynamin superfamily, Drp1, can stimulate truncated BID (tBID)-induced BAX oligomerization by interfering with mitochondrial membrane tethering and hemifusion. [97] All of these observations suggest that crosstalk between mitochondrial dynamics and the mitochondrial apoptotic pathway may exist. How BAK and BAX regulate mitochondrial fission and fusion is still not clear.

Necrosis is a different kind of cell death, characterized by organelle swelling and early plasma membrane rupture. [98] The presence of BAX and BAK proteins is required for mitochondrial permeability transition pore-dependent necrotic cell death in murine cells. [99] However, oligomerization and activation of BAK and BAX are not critical for this kind of necrotic cell death, suggesting that this type of cell death is not downstream of the mitochondrial apoptotic pathway, which depends critically on BAK or BAX oligomerization as described above. [99]

BAK and BAX expression and regulation

In addition to previous studies suggesting that BAX and BAK might have nonredundant functions, a variety of reports have suggested that their expression might also vary among different tissues. [100],[101],[102],[103],[104],[105] BAX appears to be widely expressed in normal tissues and tumors, and its promoter can be directly activainted by the tumor suppressor TP53. [106] Even though BAK expression is somewhat more varied, this pro-apoptotic BCL2 family member is expressed in a substantial fraction of cancers of the breast, [15] kidney, [107] colon, [108] head and neck, [16],[17] cervix, [18] and lung, [19] as well as Hodgkin's disease [109] and aggressive non-Hodgkin's lymphomas. [110] In view of recent results showing that BAX and BAK can undergo autoactivation in a concentration-dependent manner, [73],[74] further investigation of factors that affect BAX and BAK expression might be warranted.

Anti-apoptotic BCL2 family proteins

Structures and mechanisms of inhibiting apoptosis

The BCL2 gene, encoding the founding member of the BCL2 family of proteins, was originally discovered because of the t(14;18) chromosomal translocation in B-cell follicular lymphomas. This translocation results in fusion of the immunoglobulin heavy chain promoter and enhancer on chromosome 14 with the BCL2 gene located on chromosome 18, thus driving excessive BCL2 transcription. [111],[112],[113] The anti-apoptotic role of BCL2 was highlighted by the discovery that unlike many other previously identified oncogenes, overexpression of BCL2 promoted tumorigenesis by inhibiting cell death [114] rather than by promoting cell proliferation.

Since the discovery of BCL2, five other closely related family members, including BCLX L , MCL1, BCLW, BFL1, and BCLB (BCL2L10 in mouse) have been identified. Like BCL2, all of these five proteins are anti-apoptotic. [44],[115],[116] As shown in [Figure 2], this group of proteins shares four conserved regions of sequence homology termed BH domains. A C-terminal hydrophobic TM domain directs each of these proteins to intracellular membranes, particularly the MOM.

The anti-apoptotic BCL2 proteins possess a remarkably similar globular structure containing a so-called "BCL2 core." [116] This core consists of a bundle of eight α-helices that form a hydrophobic groove flanked by the BH1 and BH3 domains. In BCLW, the core also includes a short C-terminal helix α8 attached to the BH2 domain. The hydrophobic groove made by α3- α5 is termed the "BC groove" [116] because it binds the BH3 region of binding partners. [117] The BC groove is crucial for the biology of anti-apoptotic BCL2 family proteins, as it provides an interface for the interaction with the BH3 domain of BH3-only proteins and the apoptotic effectors BAK and BAX. Based on the structure of the BC groove, several BH3 mimics that can occupy this groove and thus inactivate these proteins' anti-apoptotic function have been developed and are currently being tested in the clinic. [118],[119],[120]

The mechanisms by which anti-apoptotic BCL2 family proteins inhibit apoptosis have been extensively characterized. As mentioned previously, anti-apoptotic BCL2 proteins bind and sequester pro-apoptotic BH3-only proteins or activated BAK/BAX, thereby preventing MOMP. [44],[117] The ability of the anti-apoptotic BCL2 proteins to bind and sequester different pro-apoptotic BCL2 family proteins varies. [121],[122],[123] Accordingly, the ability of anti-apoptotic BCL2 family proteins to protect from various stimuli depends, at least in part, on the BH3-only proteins that are synthesized or activated by the stimuli. BCL2, BCLX L , and BCLW, which bind to almost all pro-apoptotic proteins, are thought to be more potent than BCLB, BFL1, and MCL1 as far as protecting cells from apoptosis induced by a wide range of stimuli. In addition, a recent study revealed that the potency of the anti-apoptotic BCL2 family proteins reflects their expression levels. [124]

Roles of anti-apoptotic BCL2 proteins in normal development

The physiological roles of anti-apoptotic BCL2 family proteins are best demonstrated by the phenotypes of mice deficient in each of these proteins. Based on these studies, it is generally agreed that anti-apoptotic BCL2 family proteins control the survival of all mammalian cells. Mice with BCL2 gene deletion can complete embryonic development but exhibit massive apoptotic cell death in the spleen and thymus. Moreover, these BCL2(-/-) mice die of renal failure around 6 weeks of age because of abnormal death of renal epithelial progenitor cells. [125] Knockout of BCL2L1, which encodes BCLX, is embryonic lethal due to massive cell death of immature hematopoietic cells and neurons. [126] MCL1 deficiency has an even more severe physiological outcome, as MCL1(-/-) mouse embryos fail to implant in utero, [127] making it impossible to assess the role of MCL1 in development. Nonetheless, conditional MCL1 knockout impairs development and maintenance of both B and T lymphocytes. [128],[129] Moreover, specific ablation of MCL1 in cardiomyocytes results in rapid, fatal cardiac failure that can be rescued by genetic deletion of both BAX and BAK. [130],[131]

In contrast to the profound effects of BCL2, BCL2L1 and MCL1 deletion on development, deletion of BCL2L2, which encodes BCLW, does not affect mouse development except for increased apoptosis in sperm cells during spermatogenesis, which leads to male sterility. [132] Studying the function of A1, a human BFL1 homolog in mice, has been hindered by the difficulty in ablating all three functional A1 genes. Nonetheless, deletion of the A1a gene accelerates the death of granulocytes and mast cells. [133] Specific down-regulation of all three functional A1 genes in the mouse hematopoietic system impairs the survival of B lymphocytes and granulocytes without affecting T cell survival. [134] In addition, BFL1 seems important for activation-induced mast cell survival in humans. [135] The role of BCLB in mouse knockout cannot be studied because its mouse homolog (BCL2L10) carries an inactivating mutation. [136]

The role of anti-apoptotic BCL2 family proteins in tumorigenesis

Continued programmed cell death is essential for maintaining tissue homeostasis. Because many factors that block apoptosis lead to cancer development, resistance to apoptotic cell death has been regarded as one of the hallmarks of tumors. [4] Evidence accumulated over the past 25 years has shown that elevated expression of anti-apoptotic BCL2 proteins [Table 1] is one of the major contributors to oncogenesis.


High BCL2 levels have been detected in a variety of tumor types, including small cell lung, [4],[20] melanoma, [21] breast, [22] prostate, [137] colorectal, [138] and bladder cancers, [139] and especially in human lymphoid malignancies. [23],[24],[25] Elevated BCL2 expression has also been reported in acute myeloid leukemia (AML) and correlated with poor response to chemotherapy [140] although this has not been a universal finding. [28]

There are many mechanisms that contribute to BCL2 up-regulation. [111],[110],[112],[113] The t(14;18) chromosomal translocation mentioned above, [111],[112],[113] which places the BCL2 gene next to enhancer elements of the immunoglobulin heavy chain promoter, is found in 90% of follicular lymphomas and about 30% of diffuse large BCLs. [141],[142],[143] This translocation is a major mechanism for excessive BCL2 transcription. Other mechanisms include BCL2 gene rearrangement [144] and hypomethylation. [145] In addition, loss of miR-15a and miR-16, which target and repress BCL2 mRNA, occurs in more than 50% of chronic lymphocytic leukemia (CLL) as a result of chromosome deletions and mutations. [146] Conversely, overexpression of other BCL2-regulating miRNAs, including miR-195, miR-24-2, miR-365-2, and miR-204, reportedly increases the efficiency of chemotherapy in breast, [147] lung, and colon cancers. [147],[148] BCL2 levels are also regulated by ubiquitination. [149],[150],[151] The inhibitor of NF-E2-related factor 2 (INrf2) interacts with the BH2 domain of BCL2 and facilitates Cul3-Rbx1-mediated ubiquitination. Inactivating INrf2 mutations found in some lung cancer cell lines stabilize BCL2 and confer resistance to DNA damage-induced cell death. [151]


BCLX L is an important factor for tumor development. Previous studies have shown that the BCL2 L1 locus, which encodes BCLX L , is amplified in a variety of solid tumors. [33] Interestingly, the BCL2 L1 and MYC loci are often co-amplified, suggesting that BCLX L may be essential for the survival of MYC-driven tumors. [33] Importantly, BCLX L down-regulation induces apoptosis and diminishes tumorigenesis in cell lines with BCL2 L1 amplification, but not in those without this copy number gain. More recent studies in mice have further confirmed an important role for BCLX L in MYC-induced tumorigenesis. In particular, loss of a single BCL2L1 allele delays MYC-driven lymphomagenesis in mice; even normal levels of BCLX L are sufficient to accelerate this process. [152] High levels of BCLX L have been seen in a variety of human tumors including hormone-refractory prostate cancers, [26] mesenchymal breast cancers, [27] and ovarian cancers. [33],[153]

Several mechanisms that lead to elevated expression of BCLX L have been identified in addition to gene amplification. In particular, the BCR/ABL kinase, which is characteristic of chronic myeloid leukemia, phosphorylates STAT5, which subsequently binds to the promoter of the BCL2 L1 gene and enhances its transcription. [154] Several miRNAs that target the 3'- UTR of BCLX L mRNA and repress its expression have been reported as well. Decreased levels of miR-let 7c occur in hepatocellular carcinomas [155] and confer resistance of lung cancer cell lines to cisplatin. [156] Like BCL2, BCLX L is also a target of INrf2-Cul3-Rbx1-mediated ubiquitination and degradation, [151] which requires an additional molecule, phosphoglycerate mutase 5, to bridge the interaction between INrf2 and BCLX L . Whether inactivation of BCLX L ubiquitination plays a role in tumor development remains to be seen.


MCL1 up-regulation, which is seen in multiple neoplasms, likely, contributes to tumorigenesis as well. Mice expressing an MCL1 transgene develop BCLs at high frequency (85%) over a period of 2 years. [157] MCL1 also is important for the survival of acute lymphoblastic leukemia (ALL), AML [158] and CLL cells. [159] Importantly, elevated MCL1 is seen in acute leukemia at the time of relapse compared to diagnosis [28] and confers resistance to chemotherapy. [159] In addition, increased levels of MCL1 in multiple myeloma seem to correlate with disease progression. [30],[31],[32] Moreover, increased MCL1 is associated with poor prognosis in a variety of solid tumors as well. [33],[160]

MCL1 is regulated at multiple levels. MCL1 gene amplification has been observed in clinical lung and breast cancers as well as lines derived from these tumor types. [33] Loss of miR-29, which targets MCL1 mRNA and represses its translation, has been found in many cancers. [161] Decreased levels of miR-125b [162],[163] and miR-133b, [164] which target the MCL1 3'- UTR and inhibit MCL1 expression, are found in hepatocellular carcinoma and lung cancer, respectively. In addition, increased expression of USP9X, a deubiquitinase that removes Lys48-linked polyubiquitin chains from MCL1, correlates with increased MCL1 protein levels in follicular lymphoma, diffuse large BCLs and multiple myeloma. [162]


Several observations point to a potential role for BCLW in tumorigenesis. BCLW potently accelerates the development of MYC-driven leukemia in mice. [165] BCLW overexpression also renders murine lymphoid and myeloid cells resistant to several cytotoxic stimuli, including BH3 mimetics. [166],[167] Elevated levels of BCLW are frequently detected in human gastric [34],[35] and colorectal cancers [36] as well as glioblastoma multiforme. [37],[38] BCLW not only plays a role as a pro-survival protein but also promotes tumor invasion [38],[168],[169] by enhancing the expression of the transcriptional factor specificity protein 1, which subsequently upregulates the expression of matrix metalloproteinase-2. [170],[171]

BCLW levels are regulated by several processes. BCLW overexpression can result from enhanced BCLW promoter activity. [172] Amplification of the BCL2 L2 gene, which encodes BCLW, is an additional contributor for elevated BCLW expression and chemoresistance. [173],[174] Moreover, down-regulation of several miRNAs that target BCLW message has been implicated in increased BCLW expression in a number of tumor types. [163],[175],[176]


BFL1 has been studied less extensively than other anti-apoptotic BCL2 family proteins. High BFL1 levels have been detected in ALL, CLL, and DLBL [39],[40],[41],[42] and are associated with chemoresistance. A1, a homolog of human BFL1 in mice, accelerates development of MYC-driven leukemia, but it is the weakest accelerator among all of the six anti-apoptotic BCL2 family members. [165] Although A1 was initially identified as a hematopoietic tissue-specific gene that is expressed in several hematopoietic cell lineages, [177] several solid tumors aberrantly express this protein as well. Indeed, increased levels of BFL1 mRNA have been detected in a number of human solid tumors and confer resistance to chemotherapy-induced apoptosis. [178],[179],[180]

BFL1 is a direct transcriptional target of nuclear factor-kappaB (NF-kB). [181] Accordingly, activation of PI3K and extracellular signal-regulated kinase (ERK), which activate NF-kB, enhances BFL1 expression. [178],[182] In addition, BFL1 is regulated by the ubiquitin/proteasome pathway. [183],[184] Whether these regulatory mechanisms contribute to the elevated BFL1 levels in tumors remains to be elucidated.


BCLB is the least studied of the anti-apoptotic BCL2 proteins. Nonetheless, forced BCLB overexpression in mice has been shown to accelerate MYC-driven leukemia. [165] BCLB is overexpressed in human breast, prostate, gastric, colorectal, and small cell lung cancers, and high levels of this protein correlate with poor prognosis. [43] In addition, BCLB expression levels reportedly correlate with azacitidine resistance in myelodysplastic syndrome and AML. [185]

BCLB levels appear to be regulated by protein turnover. BCLB is polyubiquitinated at steady state, exhibits a half-life of only 60-70 min, and is subject to ubiquitin-dependent proteasomal degradation. [186] A K/R mutant that cannot be ubiquitinated protects cells from apoptosis induced by conventional chemotherapeutic drugs, BH3 mimetics, and TRAIL, suggesting that the level of BCLB is crucial for its protective function. Neither the E3 ligase nor the deubiquitinase for BCLB has been identified to date.

In summary, studies over the past 25 years have led to the conclusion that all six anti-apoptotic BCL2 family proteins can facilitate tumorigenesis and confer resistance to various treatments. The anti-apoptotic (or pro-survival) capacity varies among the family members, but it is generally agreed that BCL2, BCLX L , and MCL1 have a stronger protective effect against death signaling than BCLW, BFL1, and BCLB. This variation in potency may reflect binding selectivity and affinity for pro-apoptotic BH3-only proteins, BAK and BAX, as well as the levels of each anti-apoptotic protein. Relative potencies of the anti-apoptotic proteins may also depend on cellular context, including phosphorylation and ubiquitylation events that modify BCL2 family proteins, as well as the nature of the cytotoxic signaling.

BH3-only proteins

Activators and sensitizers

The most important role of BH3-only proteins such as BIM, PUMA, BID, and NOXA is to act as integrators of various signals to initiate MOMP. The BH3-only proteins are activated by distinct cytotoxic stimuli in various ways, including enhanced transcription and posttranslational modifications. [187] Microtubule- or actin-targeting agents disrupt cytoskeleton integrity and release some of the BH3-only proteins (such as BIM and BMF) from their interaction partners, allowing them to translocate to mitochondria and promote MOMP. [188],[189],[190] Tyrosine kinase inhibitors upregulate BIM and PUMA through the PI3K-AKT pathway to induce MOMP. [191] In short, a variety of cellular stresses are integrated by BH3-only proteins.

As mentioned previously, these BH3-only proteins can be divided into direct activators and sensitizers. [54],[55],[56] As shown in [Figure 3], BIM and tBID were first defined as direct activators because of their ability to directly induce BAK and/or BAX activation. [56] PUMA was also able to directly induce BAK/BAX activation although the efficiency is lower than BIM. [60],[192] Moreover, BID/BIM/PUMA triple knockout mice displayed developmental defects that were reportedly similar to BAK/BAX double knockout mice. In addition, BID/BIM/PUMA triple knockout cells exhibited resistance to a variety of apoptotic stimuli, such as potassium deprivation and etoposide although they were sensitive to other triggers such as ionizing radiation and dexamethasone. [193]
Figure 3. Binding profiles BH3-only proteins to anti-apoptotic BCL2 family proteins and BAX and BAK. The BH3-only proteins BIM, PUMA, truncated BID, NOXA, and BAD can either inhibit the anti-apoptotic BCL2 family proteins (solid line), or directly activate BAK and BAX (dashed line). The thickness of each line reflects the reported strength of the interaction. BCL2: B-cell lymphoma-2; BH3: B-cell lymphoma-2 homology 3; BAX: B-cell lymphoma-2-associated X; BAK: BCL2 antagonist/killer; BCLXL: B-cell lymphoma-X large; MCL1: Myeloid cell leukemia 1

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It had been unclear whether tBID, BIM, and PUMA are the only direct activators. Several studies also identified NOXA as a direct activator that can bind BAK or BAX and induce the BAK/BAX-mediated liposome release in vitro. [51],[192] Structural studies, however, showed no direct interaction of NOXA BH3 peptide with BAK or BAX. [53],[67],[72] The difference between these two sets of studies might arise from the use of BH3 peptide versus full-length protein. More recently, study of BID/BIM/PUMA/NOXA quadruple knockout mouse cells revealed increased resistance to most apoptotic stimuli, including cytokine withdrawal, etoposide, dexamethasone, and irradiation, compared with BID/BIM/PUMA triple knockout cells, providing further support for the concept that NOXA plays a role in BAK/BAX activation in intact murine cells. [73] Moreover, the observation that NOXA directly interacts with BAK and BAX in living cells also suggests that full-length NOXA may serve as a direct activator. [194] BIK, BMF, and HRK have also been reported to directly activate BAK/BAX albeit with lower affinities. [192],[195] That leaves the BH3-only protein BAD as the only pure sensitizer that reportedly binds solely to anti-apoptotic BCL2 family members, thereby releasing activators. When compared, BIM and tBID show greater ability than other BH3-only proteins to activate BAK/BAX. [51],[60] Interestingly, while BIM preferentially activates BAX, tBID preferentially activates BAK. [196]

Inhibitors of anti-apoptotic BCL2 family proteins

Despite varied activity as activators, all of the BH3-only proteins have the ability to act as sensitizers. Specifically, activator BH3-only proteins can not only interact with BAK and BAX but also bind the BH3 binding groove of anti-apoptotic BCL2 proteins, thereby causing release of the other activator BH3-only proteins as well as activated BAK or BAX. Surface plasma resonance assays measuring binding of anti-apoptotic BCL2 proteins without TM domains to immobilized BH3 peptides from BH3-only proteins have shown that BH3 peptides are not all bound equally by anti-apoptotic BCL2 family proteins. [58],[121] Based on observed differences in binding affinities, it was originally thought that BIM and BID could induce more apoptosis because of their ability to bind all anti-apoptotic BCL2 family proteins. [57],[58] The actual situation, however, is more nuanced than this [Figure 3]. As summarized in [Table 1], the highest affinity interactions involve binding of BIM, PUMA, and BID BH3 domains to all of the anti-apoptotic BCL2 family proteins; BAD and BMF to BCL2, BCLX L , and BCLW; NOXA to MCL1 and A1; and BIK and HRK to BCLX L , BCLW, and A1. [58],[121] Nonetheless, it is important to emphasize that abundance of the anti-apoptotic proteins also plays a role. Lower affinity interactions (e.g., with dissociation constants in the submicromolar range) can be detected, e.g., between NOXA and BCLX L or BCL2; these interactions can play a role in modulating drug sensitivity under conditions where large amounts of the "less preferred" anti-apoptotic BCL2 family members are present.

Mutations in the BCL2 gene can also affect these binding specificities. In particular, some of the mutant BCL2 proteins found in lymphoma cell lines display enhanced affinity for NOXA, [197] which contributes to bortezomib resistance of cells harboring these mutations. A systematic study of BCL2 mutations in follicular lymphoma also found that some mutant BCL2 proteins have increased affinities for BIM and PUMA, and the patients bearing these BCL2 mutations have increased risk of progression to more aggressive lymphoma and subsequent death. [198] Moreover, CDK1-mediated BCL2 phosphorylation also increases its affinity for BIM and BAK when the cells are treated with microtubule-targeted chemotherapeutic agents. [61]

Nonapoptotic functions of BH3-only proteins

BH3-only proteins have also been reported to have nonapoptotic functions. [199] This can vary with the BH3-only protein and the cellular context.

Several BH3-only proteins have been implicated in cell cycle regulation. BAD can regulate the cell cycle through its interactions with BCLX L and BCL2, which reportedly cause cell cycle arrest in S phase. [200] BIM is involved in G1/S cell cycle arrest, which is mediated by ERK phosphorylation when cells are deprived of adhesion-mediated signaling and induced to undergo anoikis. [201]

BAD has been reported to reside in a glucokinase-containing complex where it regulates glucokinase activity, mitochondrial respiration, ATP production, and pancreatic beta cell survival. [202],[203],[204] Furthermore, BAD is phosphorylated by the inhibitor of kappa B kinase complex independent of NF-kB activation and suppresses tumor necrosis factor-α induced apoptosis. [205]

BH3-only proteins can also regulate autophagy. BECLIN1 interacts with ATG14 L and VPS34, thereby inducing phagophore formation. [206] BECLIN1 and BECLIN2 also contain BH3 domains that can bind to anti-apoptotic BCL2 family proteins. [206],[207],[208] Because BECLIN1 binds to anti-apoptotic BCL2 family proteins with much less efficiency than other BH3-only proteins, [208],[209] BAD and NOXA have been reported to induce autophagy by displacing BECLIN1 from BCL2 [208] or MCL1, [210] respectively. However, it has been more recently suggested that the effect of anti-apoptotic BCL2 family proteins on autophagy occurs downstream of the mitochondrial apoptotic pathway. [211]

The BH3-only protein BID has been reported to be involved in the DNA damage response. [212],[213],[214] BID is phosphorylated by ataxia telangiectasia mutated following induction of DNA double-strand breaks. However, BID(-/-) murine cells undergo cell-cycle arrest after DNA damage that is indistinguishable from the cell cycle response of wild-type cells, arguing against a major role for Bid in the DNA damage response. [215] Although this inconsistency might reflect differences in the method of immortalizing the cell lines studied, [216] consistent evidence against a role for Bid in DNA damaged-induced apoptosis was obtained from nine distinct cell types. [215]

Finally, BIM and PUMA have been reported to play important roles in endoplasmic reticulum (ER) stress. ER stress caused by misfolded proteins induces BIM up-regulation and phosphorylation, which are mediated by CHOP-C/EBPα and are essential for ER stress-induced apoptosis. [217] BIM and PUMA also regulate hyperglycemia-induced ER and oxidative stress in type 2 diabetes. [218] Moreover, BIM and PUMA can interact with IRE1α and inhibit its effects on XBP-1 mRNA splicing, which can in turn regulates ER stress-regulated antibody secretion by primary B cells. [219]

  Future Perspectives Top

Since the discovery of BCL2 about 30 years ago, [111],[112],[113] great progress has been made in understanding the structures, normal functions, and pathological roles of the BCL2 family proteins. Recent studies have provided the structures of symmetric dimers of activated BAK and BAX. Importantly, however, there are still a lot of unsolved questions regarding this family of proteins. The structure of higher order BAK and BAX oligomers is still unknown as is the mechanism by which these oligomers cause MOMP. Moreover, BCL2 family proteins have also been implicated in mitochondrial dynamics, cell cycle regulation, the ER stress response, autophagy, and DNA damage responses although some of these nonapoptotic functions need to be further clarified. Finally, while selective antagonists of BCL2, BCLX L , and MCL1 have been identified, only the selective BCL2 antagonist is progressing rapidly in the clinic. Further studies are needed to identify more drug-like inhibitors of BCLX L and MCL1. Whether the recent structural information regarding BAX and BAK activation can also be utilized to develop new therapeutic agents, e.g. for degenerative diseases also remains to be seen.

Financial support and sponsorship

The study was supported by Hundred-Talent Program of Chinese Academy of Sciences, and the National Natural Science Foundation of China (No. 81572948).

Conflicts of interest

There are no conflicts of interest.

  References Top

Martinou JC, Youle RJ. Mitochondria in apoptosis: bcl-2 family members and mitochondrial dynamics. Dev Cell 2011; 21 (1): 92-101.  Back to cited text no. 1
Hyman BT, Yuan J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 2012; 13 (6): 395-406.  Back to cited text no. 2
Meng XW, Lee SH, Kaufmann SH. Apoptosis in the treatment of cancer: a promise kept? Curr Opin Cell Biol 2006; 18 (6): 668-76.  Back to cited text no. 3
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (5): 646-74.  Back to cited text no. 4
Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 2003; 22 (53): 8590-607.  Back to cited text no. 5
Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 2003; 22 (47): 7414-30.  Back to cited text no. 6
Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108 (2): 153-64.  Back to cited text no. 7
Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res 2000; 256 (1): 42-9.  Back to cited text no. 8
Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev cancer 2002; 2 (6): 420-30.  Back to cited text no. 9
Kaufmann SH, Steensma DP. On the TRAIL of a new therapy for leukemia. Leukemia 2005; 19 (12): 2195-202.  Back to cited text no. 10
Yan N, Shi Y. Mechanisms of apoptosis through structural biology. Annu Rev Cell Dev Biol 2005; 21: 35-56.  Back to cited text no. 11
Meng XW, Peterson KL, Dai H, Schneider P, Lee SH, Zhang JS, Koenig A, Bronk S, Billadeau DD, Gores GJ, Kaufmann SH. High cell surface death receptor expression determines type I versus type II signaling. J Biol Chem 2011; 286 (41): 35823-33.  Back to cited text no. 12
Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem 2004; 73: 87-106.  Back to cited text no. 13
Ekert PG, Vaux DL. The mitochondrial death squad: hardened killers or innocent bystanders? Curr Opin Cell Biol 2005; 17 (6): 626-30.  Back to cited text no. 14
Eguchi H, Suga K, Saji H, Toi M, Nakachi K, Hayashi SI. Different expression patterns of Bcl-2 family genes in breast cancer by estrogen receptor status with special reference to pro-apoptotic Bak gene. Cell Death Differ 2000; 7 (5): 439-46.  Back to cited text no. 15
Chen GG, Vlantis AC, Chak EC, Liu HC, Tong MC, van Hasselt CA. The expression of Bcl-2 family proteins and spontaneous apoptosis in laryngeal carcinomas. Oncol Res 2006; 16 (6): 273-80.  Back to cited text no. 16
Schoelch ML, Le QT, Silverman S Jr., McMillan A, Dekker NP, Fu KK, Ziober BL, Regezi JA. Apoptosis-associated proteins and the development of oral squamous cell carcinoma. Oral Oncol 1999; 35 (1): 77-85.  Back to cited text no. 17
Cheung TH, Chung TK, Lo KW, Yu MY, Krajewski S, Reed JC, Wong YF. Apotosis-related proteins in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix. Gynecol Oncol 2002; 86 (1): 14-8.  Back to cited text no. 18
Berrieman HK, Smith L, O'Kane SL, Campbell A, Lind MJ, Cawkwell L. The expression of Bcl-2 family proteins differs between nonsmall cell lung carcinoma subtypes. Cancer 2005; 103 (7): 1415-9.  Back to cited text no. 19
Jiang SX, Sato Y, Kuwao S, Kameya T. Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas. J Pathol 1995; 177 (2): 135-8.  Back to cited text no. 20
Grover R, Wilson GD. Bcl-2 expression in malignant melanoma and its prognostic significance. Eur J Surg Oncol 1996; 22 (4): 347-9.  Back to cited text no. 21
Joensuu H, Pylkkanen L, Toikkanen S. Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 1994; 145 (5): 1191-8.  Back to cited text no. 22
Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene 2008; 27 (50): 6398-406.  Back to cited text no. 23
Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood 2008; 111 (7): 3322-30.  Back to cited text no. 24
Scarfò L, Ghia P. Reprogramming cell death: bcl2 family inhibition in hematological malignancies. Immunol Lett 2013; 155 (1-2): 36-9.  Back to cited text no. 25
Castilla C, Congregado B, Chinchon D, Torrubia FJ, Japon MA, Saez C. Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak. Endocrinology 2006; 147 (10): 4960-7.  Back to cited text no. 26
Keitel U, Scheel A, Thomale J, Halpape R, Kaulfuss S, Scheel C, Dobbelstein M. Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation. Oncotarget 2014; 5 (23): 11778-91.  Back to cited text no. 27
Kaufmann SH, Karp JE, Svingen PA, Krajewski S, Burke PJ, Gore SD, Reed JC. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood 1998; 91 (3): 991-1000.  Back to cited text no. 28
Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, Wang HG, Zhang X, Bullrich F, Croce CM, Rai K, Hines J, Reed JC. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91 (9): 3379-89.  Back to cited text no. 29
Quinn BA, Dash R, Azab B, Sarkar S, Das SK, Kumar S, Oyesanya RA, Dasgupta S, Dent P, Grant S, Rahmani M, Curiel DT, Dmitriev I, Hedvat M, Wei J, Wu B, Stebbins JL, Reed JC, Pellecchia M, Sarkar D, Fisher PB. Targeting Mcl-1 for the therapy of cancer. Expert Opin Investig Drugs 2011; 20 (10): 1397-411.  Back to cited text no. 30
Wuilleme-Toumi S, Robillard N, Gomez P, Moreau P, Le Gouill S, Avet-Loiseau H, Harousseau JL, Amiot M, Bataille R. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia 2005; 19 (7): 1248-52.  Back to cited text no. 31
Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P. Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol 2007; 20 (4): 416-26.  Back to cited text no. 32
Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463 (7283): 899-905.  Back to cited text no. 33
Lee HW, Lee SS, Lee SJ, Um HD. Bcl-w is expressed in a majority of infiltrative gastric adenocarcinomas and suppresses the cancer cell death by blocking stress-activated protein kinase/c-Jun NH2-terminal kinase activation. Cancer Res 2003; 63 (5): 1093-100.  Back to cited text no. 34
Pritchard DM, Print C, O'Reilly L, Adams JM, Potten CS, Hickman JA. Bcl-w is an important determinant of damage-induced apoptosis in epithelia of small and large intestine. Oncogene 2000; 19 (34): 3955-9.  Back to cited text no. 35
Wilson JW, Nostro MC, Balzi M, Faraoni P, Cianchi F, Becciolini A, Potten CS. Bcl-w expression in colorectal adenocarcinoma. Br J Cancer 2000; 82 (1): 178-85.  Back to cited text no. 36
Hoelzinger DB, Mariani L, Weis J, Woyke T, Berens TJ, McDonough WS, Sloan A, Coons SW, Berens ME. Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia 2005; 7 (1): 7-16.  Back to cited text no. 37
Lee WS, Woo EY, Kwon J, Park MJ, Lee JS, Han YH, Bae IH. Bcl-w Enhances Mesenchymal Changes and Invasiveness of Glioblastoma Cells by Inducing Nuclear Accumulation of β-Catenin. PLoS One 2013; 8 (6): e68030.  Back to cited text no. 38
Nagy B, Lundán T, Larramendy ML, Aalto Y, Zhu Y, Niini T, Edgren H, Ferrer A, Vilpo J, Elonen E, Vettenranta K, Franssila K, Knuutila S. Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol 2003; 120 (3): 434-41.  Back to cited text no. 39
Mahadevan D, Spier C, Della Croce K, Miller S, George B, Riley C, Warner S, Grogan TM, Miller TP. Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures. Mol Cancer Ther 2005; 4 (12): 1867-79.  Back to cited text no. 40
Piva R, Pellegrino E, Mattioli M, Agnelli L, Lombardi L, Boccalatte F, Costa G, Ruggeri BA, Cheng M, Chiarle R, Palestro G, Neri A, Inghirami G. Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. J Clin Invest 2006; 116 (12): 3171-82.  Back to cited text no. 41
Morales AA, Olsson A, Celsing F, Osterborg A, Jondal M, Osorio LM. High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia. Int J Cancer 2005; 113 (5): 730-7.  Back to cited text no. 42
Krajewska M, Kitada S, Winter JN, Variakojis D, Lichtenstein A, Zhai D, Cuddy M, Huang X, Luciano F, Baker CH, Kim H, Shin E, Kennedy S, Olson AH, Badzio A, Jassem J, Meinhold-Heerlein I, Duffy MJ, Schimmer AD, Tsao M, Brown E, Sawyers A, Andreeff M, Mercola D, Krajewski S, Reed JC. Bcl-B expression in human epithelial and nonepithelial malignancies. Clin Cancer Res 2008; 14 (10): 3011-21.  Back to cited text no. 43
Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15 (1): 49-63.  Back to cited text no. 44
Echeverry N, Bachmann D, Ke F, Strasser A, Simon HU, Kaufmann T. Intracellular localization of the BCL-2 family member BOK and functional implications. Cell Death Differ 2013; 20 (6): 785-99.  Back to cited text no. 45
Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell 2006; 24 (5): 677-88.  Back to cited text no. 46
Wang H, Takemoto C, Akasaka R, Uchikubo-Kamo T, Kishishita S, Murayama K, Terada T, Chen L, Liu ZJ, Wang BC, Sugano S, Tanaka A, Inoue M, Kigawa T, Shirouzu M, Yokoyama S. Novel dimerization mode of the human Bcl-2 family protein Bak, a mitochondrial apoptosis regulator. J Struct Biol 2009; 166 (1): 32-7.  Back to cited text no. 47
Suzuki M, Youle RJ, Tjandra N. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 2000; 103 (4): 645-54.  Back to cited text no. 48
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX activation is initiated at a novel interaction site. Nature 2008; 455 (7216): 1076-81.  Back to cited text no. 49
Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD. BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell 2010; 40 (3): 481-92.  Back to cited text no. 50
Dai H, Smith A, Meng XW, Schneider PA, Pang YP, Kaufmann SH. Transient binding of an activator BH3 domain to the Bak BH3-binding groove initiates Bak oligomerization. J Cell Biol 2011; 194 (1): 39-48.  Back to cited text no. 51
Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 2009; 36 (3): 487-99.  Back to cited text no. 52
Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 2013; 152 (3): 519-31.  Back to cited text no. 53
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14 (16): 2060-71.  Back to cited text no. 54
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005; 17 (4): 525-35.  Back to cited text no. 55
Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer cell 2002; 2 (3): 183-92.  Back to cited text no. 56
Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 2007; 315 (5813): 856-9.  Back to cited text no. 57
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005; 17 (3): 393-403.  Back to cited text no. 58
Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, Dillon CP, Green DR. A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 2011; 44 (4): 517-31.  Back to cited text no. 59
Dai H, Pang YP, Ramirez-Alvarado M, Kaufmann SH. Evaluation of the BH3-only protein Puma as a direct Bak activator. J Biol Chem 2014; 289 (1): 89-99.  Back to cited text no. 60
Dai H, Ding H, Meng XW, Lee SH, Schneider PA, Kaufmann SH. Contribution of Bcl-2 phosphorylation to Bak binding and drug resistance. Cancer Res 2013; 73 (23): 6998-7008.  Back to cited text no. 61
Weber K, Harper N, Schwabe J, Cohen GM. BIM-mediated membrane insertion of the BAK pore domain is an essential requirement for apoptosis. Cell Rep 2013; 5 (2): 409-20.  Back to cited text no. 62
Edwards AL, Gavathiotis E, LaBelle JL, Braun CR, Opoku-Nsiah KA, Bird GH, Walensky LD. Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3. Chem Biol 2013; 20 (7): 888-902.  Back to cited text no. 63
Lindner AU, Concannon CG, Boukes GJ, Cannon MD, Llambi F, Ryan D, Boland K, Kehoe J, McNamara DA, Murray F, Kay EW, Hector S, Green DR, Huber HJ, Prehn JH. Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapy. Cancer Res 2013; 73 (2): 519-28.  Back to cited text no. 64
Mérino D, Giam M, Hughes PD, Siggs OM, Heger K, O'Reilly LA, Adams JM, Strasser A, Lee EF, Fairlie WD, Bouillet P. The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. J Cell Biol 2009; 186 (3): 355-62.  Back to cited text no. 65
Pang YP, Dai H, Smith A, Meng XW, Schneider PA, Kaufmann SH. Bak conformational changes induced by ligand binding: insight into BH3 domain binding and Bak homo-oligomerization. Sci Rep 2012; 2: 257.  Back to cited text no. 66
Brouwer JM, Westphal D, Dewson G, Robin AY, Uren RT, Bartolo R, Thompson GV, Colman PM, Kluck RM, Czabotar PE. Bak core and latch domains separate during activation, and freed core domains form symmetric homodimers. Mol Cell 2014; 55 (6): 938-46.  Back to cited text no. 67
Leshchiner ES, Braun CR, Bird GH, Walensky LD. Direct activation of full-length proapoptotic BAK. Proc Natl Acad Sci U S A 2013; 110 (11): E986-95.  Back to cited text no. 68
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303 (5660): 1010-4.  Back to cited text no. 69
Sainski AM, Dai H, Natesampillai S, Pang YP, Bren GD, Cummins NW, Correia C, Meng XW, Tarara JE, Ramirez-Alvarado M, Katzmann DJ, Ochsenbauer C, Kappes JC, Kaufmann SH, Badley AD. Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation. J Cell Biol 2014; 206 (7): 867-76.  Back to cited text no. 70
Hilgendorf KI, Leshchiner ES, Nedelcu S, Maynard MA, Calo E, Ianari A, Walensky LD, Lees JA. The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes Dev 2013; 27 (9): 1003-15.  Back to cited text no. 71
Moldoveanu T, Grace CR, Llambi F, Nourse A, Fitzgerald P, Gehring K, Kriwacki RW, Green DR. BID-induced structural changes in BAK promote apoptosis. Nat Struct Mol Biol 2013; 20 (5): 589-97.  Back to cited text no. 72
Chen HC, Kanai M, Inoue-Yamauchi A, Tu HC, Huang Y, Ren D, Kim H, Takeda S, Reyna DE, Chan PM, Ganesan YT, Liao CP, Gavathiotis E, Hsieh JJ, Cheng EH. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 2015; 17 (10): 1270-81.  Back to cited text no. 73
Dai H, Ding H, Meng XW, Peterson KL, Schneider PA, Karp JE, Kaufmann SH. Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells. Genes Dev 2015; 29 (20): 2140-52.  Back to cited text no. 74
Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA. Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. J Cell Biol 1999; 144 (5): 903-14.  Back to cited text no. 75
Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3: groove interactions. Mol Cell 2008; 30 (3): 369-80.  Back to cited text no. 76
Dewson G, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci 2009; 122(Pt 16): 2801-8.  Back to cited text no. 77
Dewson G, Ma S, Frederick P, Hockings C, Tan I, Kratina T, Kluck RM. Bax dimerizes via a symmetric BH3: groove interface during apoptosis. Cell Death Differ 2012; 19 (4): 661-70.  Back to cited text no. 78
Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol Cell 2009; 36 (4): 696-703.  Back to cited text no. 79
Ma S, Hockings C, Anwari K, Kratina T, Fennell S, Lazarou M, Ryan MT, Kluck RM, Dewson G. Assembly of the Bak apoptotic pore: a critical role for the Bak protein α6 helix in the multimerization of homodimers during apoptosis. J Biol Chem 2013; 288 (36): 26027-38.  Back to cited text no. 80
Alsop AE, Fennell SC, Bartolo RC, Tan IK, Dewson G, Kluck RM. Dissociation of Bak α1 helix from the core and latch domains is required for apoptosis. Nat Commun 2015; 6: 6841.  Back to cited text no. 81
Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, Eisenberg D. The crystal structure of diphtheria toxin. Nature 1992; 357 (6375): 216-22.  Back to cited text no. 82
Elkins P, Bunker A, Cramer WA, Stauffacher CV. A mechanism for toxin insertion into membranes is suggested by the crystal structure of the channel-forming domain of colicin E1. Structure 1997; 5 (3): 443-58.  Back to cited text no. 83
Parker MW, Feil SC. Pore-forming protein toxins: from structure to function. Prog Biophys Mol Biol 2005; 88 (1): 91-142.  Back to cited text no. 84
Walker B, Bayley H. Key residues for membrane binding, oligomerization, and pore forming activity of staphylococcal alpha-hemolysin identified by cysteine scanning mutagenesis and targeted chemical modification. J Biol Chem 1995; 270 (39): 23065-71.  Back to cited text no. 85
Annis MG, Soucie EL, Dlugosz PJ, Cruz-Aguado JA, Penn LZ, Leber B, Andrews DW. Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J 2005; 24 (12): 2096-103.  Back to cited text no. 86
Fuertes G, García-Sáez AJ, Esteban-Martín S, Giménez D, Sánchez-Muñoz OL, Schwille P, Salgado J. Pores formed by Baxalpha5 relax to a smaller size and keep at equilibrium. Biophys J 2010; 99 (9): 2917-25.  Back to cited text no. 87
Garcia-Saez AJ, Coraiola M, Serra MD, Mingarro I, Muller P, Salgado J. Peptides corresponding to helices 5 and 6 of Bax can independently form large lipid pores. FEBS J 2006; 273 (5): 971-81.  Back to cited text no. 88
Qian S, Wang W, Yang L, Huang HW. Structure of transmembrane pore induced by Bax-derived peptide: evidence for lipidic pores. Proc Natl Acad Sci U S A 2008; 105 (45): 17379-83.  Back to cited text no. 89
Oh KJ, Singh P, Lee K, Foss K, Lee S, Park M, Lee S, Aluvila S, Park M, Singh P, Kim RS, Symersky J, Walters DE. Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3-BH3 contact interface in BAK homo-oligomers. J Biol Chem 2010; 285 (37): 28924-37.  Back to cited text no. 90
Westphal D, Dewson G, Menard M, Frederick P, Iyer S, Bartolo R, Gibson L, Czabotar PE, Smith BJ, Adams JM, Kluck RM. Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane. Proc Natl Acad Sci U S A 2014; 111 (39): E4076-85.  Back to cited text no. 91
Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science 2012; 337 (6098): 1062-5.  Back to cited text no. 92
Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 2001; 1 (4): 515-25.  Back to cited text no. 93
Karbowski M, Arnoult D, Chen H, Chan DC, Smith CL, Youle RJ. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol 2004; 164 (4): 493-9.  Back to cited text no. 94
Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ. Role of Bax and Bak in mitochondrial morphogenesis. Nature 2006; 443 (7112): 658-62.  Back to cited text no. 95
Arnoult D, Rismanchi N, Grodet A, Roberts RG, Seeburg DP, Estaquier J, Sheng M, Blackstone C. Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 2005; 15 (23): 2112-8.  Back to cited text no. 96
Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basañez G, Meda P, Martinou JC. Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 2010; 142 (6): 889-901.  Back to cited text no. 97
Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004; 116 (2): 205-19.  Back to cited text no. 98
Karch J, Kwong JQ, Burr AR, Sargent MA, Elrod JW, Peixoto PM, Martinez-Caballero S, Osinska H, Cheng EH, Robbins J, Kinnally KW, Molkentin JD. Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice. Elife 2013; 2: e00772.  Back to cited text no. 99
Kandasamy K, Srinivasula SM, Alnemri ES, Thompson CB, Korsmeyer SJ, Bryant JL, Srivastava RK. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res 2003; 63 (7): 1712-21.  Back to cited text no. 100
Cartron PF, Juin P, Oliver L, Meflah K, Vallette FM. Impact of proapoptotic proteins Bax and Bak in tumor progression and response to treatment. Expert Rev Anticancer Ther 2003; 3 (4): 563-70.  Back to cited text no. 101
Dai H, Meng XW, Lee SH, Schneider PA, Kaufmann SH. Context-dependent Bcl-2/Bak interactions regulate lymphoid cell apoptosis. J Biol Chem 2009; 284 (27): 18311-22.  Back to cited text no. 102
Degli Esposti M, Dive C. Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun 2003; 304 (3): 455-61.  Back to cited text no. 103
Martin LJ, Liu Z, Pipino J, Chestnut B, Landek MA. Molecular regulation of DNA damage-induced apoptosis in neurons of cerebral cortex. Cereb Cortex 2009; 19 (6): 1273-93.  Back to cited text no. 104
Rotolo JA, Maj JG, Feldman R, Ren D, Haimovitz-Friedman A, Cordon-Cardo C, Cheng EH, Kolesnick R, Fuks Z. Bax and Bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa. Int J Radiat Oncol Biol Phys 2008; 70 (3): 804-15.  Back to cited text no. 105
Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994; 9 (6): 1799-805.  Back to cited text no. 106
Pammer J, Exner M, Regele H, Haitel A, Weninger W, Horvat R, Susani M. Expression of bcl-2, bcl-x, Bax and Bak in renal parenchyma, oncocytomas and renal cell carcinomas. Pathol Res Pract 1998; 194 (12): 837-45.  Back to cited text no. 107
Ogura E, Senzaki H, Yamamoto D, Yoshida R, Takada H, Hioki K, Tsubura A. Prognostic significance of Bcl-2, Bcl-xL/S, Bax and Bak expressions in colorectal carcinomas. Oncol Rep 1999; 6 (2): 365-9.  Back to cited text no. 108
Brousset P, Krajewski S, Schlaifer D, Reed JC, Delsol G. Detection of the cell death-inducing protein BAK in Reed-Sternberg cells of Hodgkin's disease. Leuk Lymphoma 1999; 34 (5-6): 581-4.  Back to cited text no. 109
Pagnano KB, Silva MD, Vassallo J, Aranha FJ, Saad ST. Apoptosis-regulating proteins and prognosis in diffuse large B cell non-Hodgkin's lymphomas. Acta Haematol 2002; 107 (1): 29-34.  Back to cited text no. 110
Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science 1985; 228 (4706): 1440-3.  Back to cited text no. 111
Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ. Cloning the chromosomal breakpoint of t (14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985; 41 (3): 899-906.  Back to cited text no. 112
Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t (14;18) translocation. Cell 1986; 47 (1): 19-28.  Back to cited text no. 113
Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335 (6189): 440-2.  Back to cited text no. 114
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9 (1): 47-59.  Back to cited text no. 115
Moldoveanu T, Follis AV, Kriwacki RW, Green DR. Many players in BCL-2 family affairs. Trends Biochem Sci 2014; 39 (3): 101-11.  Back to cited text no. 116
Hinds MG, Lackmann M, Skea GL, Harrison PJ, Huang DC, Day CL. The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. EMBO J 2003; 22 (7): 1497-507.  Back to cited text no. 117
Correia C, Lee SH, Meng XW, Vincelette ND, Knorr KL, Ding H, Nowakowski GS, Dai H, Kaufmann SH. Emerging understanding of Bcl-2 biology: implications for neoplastic progression and treatment. Biochim Biophys Acta 2015; 1853 (7): 1658-71.  Back to cited text no. 118
Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 2008; 7 (12): 989-1000.  Back to cited text no. 119
Billard C. BH3 mimetics: status of the field and new developments. Mol Cancer Ther 2013; 12 (9): 1691-700.  Back to cited text no. 120
Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer cell 2006; 9 (5): 351-65.  Back to cited text no. 121
Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005; 19 (11): 1294-305.  Back to cited text no. 122
Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 2006; 8 (12): 1348-58.  Back to cited text no. 123
Rooswinkel RW, van de Kooij B, de Vries E, Paauwe M, Braster R, Verheij M, Borst J. Antiapoptotic potency of Bcl-2 proteins primarily relies on their stability, not binding selectivity. Blood 2014; 123 (18): 2806-15.  Back to cited text no. 124
Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993; 75 (2): 229-40.  Back to cited text no. 125
Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 1995; 267 (5203): 1506-10.  Back to cited text no. 126
Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 2000; 14 (1): 23-7.  Back to cited text no. 127
Vikstrom I, Carotta S, Lüthje K, Peperzak V, Jost PJ, Glaser S, Busslinger M, Bouillet P, Strasser A, Nutt SL, Tarlinton DM. Mcl-1 is essential for germinal center formation and B cell memory. Science 2010; 330 (6007): 1095-9.  Back to cited text no. 128
Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 2003; 426 (6967): 671-6.  Back to cited text no. 129
Thomas RL, Roberts DJ, Kubli DA, Lee Y, Quinsay MN, Owens JB, Fischer KM, Sussman MA, Miyamoto S, Gustafsson ÅB. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev 2013; 27 (12): 1365-77.  Back to cited text no. 130
Wang X, Bathina M, Lynch J, Koss B, Calabrese C, Frase S, Schuetz JD, Rehg JE, Opferman JT. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev 2013; 27 (12): 1351-64.  Back to cited text no. 131
Print CG, Loveland KL, Gibson L, Meehan T, Stylianou A, Wreford N, de Kretser D, Metcalf D, Köntgen F, Adams JM, Cory S. Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci U S A 1998; 95 (21): 12424-31.  Back to cited text no. 132
Hamasaki A, Sendo F, Nakayama K, Ishida N, Negishi I, Nakayama K, Hatakeyama S. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med 1998; 188 (11): 1985-92.  Back to cited text no. 133
Ottina E, Grespi F, Tischner D, Soratroi C, Geley S, Ploner A, Reichardt HM, Villunger A, Herold MJ. Targeting antiapoptotic A1/Bfl-1 by in vivo RNAi reveals multiple roles in leukocyte development in mice. Blood 2012; 119 (25): 6032-42.  Back to cited text no. 134
Ekoff M, Lyberg K, Krajewska M, Arvidsson M, Rak S, Reed JC, Harvima I, Nilsson G. Anti-apoptotic BFL-1 is the major effector in activation-induced human mast cell survival. PLoS One 2012; 7 (6): e39117.  Back to cited text no. 135
Rautureau GJ, Day CL, Hinds MG. The structure of Boo/Diva reveals a divergent Bcl-2 protein. Proteins 2010; 78 (9): 2181-6.  Back to cited text no. 136
McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992; 52 (24): 6940-4.  Back to cited text no. 137
Sinicrope FA, Hart J, Michelassi F, Lee JJ. Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma. Clin Cancer Res 1995; 1 (10): 1103-10.  Back to cited text no. 138
Gazzaniga P, Gradilone A, Vercillo R, Gandini O, Silvestri I, Napolitano M, Albonici L, Vincenzoni A, Gallucci M, Frati L, Agliano AM. Bcl-2/bax mRNA expression ratio as prognostic factor in low-grade urinary bladder cancer. Int J Cancer 1996; 69 (2): 100-4.  Back to cited text no. 139
Bincoletto C, Saad ST, da Silva ES, Queiroz ML. Haematopoietic response and bcl-2 expression in patients with acute myeloid leukaemia. Eur J Haematol 1999; 62 (1): 38-42.  Back to cited text no. 140
Weiss LM, Warnke RA, Sklar J, Cleary ML. Molecular analysis of the t (14;18) chromosomal translocation in malignant lymphomas. N Engl J Med 1987; 317 (19): 1185-9.  Back to cited text no. 141
Ngan BY, Chen-Levy Z, Weiss LM, Warnke RA, Cleary ML. Expression in non-Hodgkin's lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. N Engl J Med 1988; 318 (25): 1638-44.  Back to cited text no. 142
LeBrun DP, Ngan BY, Weiss LM, Huie P, Warnke RA, Cleary ML. The bcl-2 oncogene in Hodgkin's disease arising in the setting of follicular non-Hodgkin's lymphoma. Blood 1994; 83 (1): 223-30.  Back to cited text no. 143
Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, Popplewell L, Offit K, Jhanwar SC, Chaganti RS. Chromosomal and gene amplification in diffuse large B-cell lymphoma. Blood 1998; 92 (1): 234-40.  Back to cited text no. 144
Tymianski M, Wallace MC, Spigelman I, Uno M, Carlen PL, Tator CH, Charlton MP. Cell-permeant Ca2+chelators reduce early excitotoxic and ischemic neuronal injury in vitro and in vivo. Neuron 1993; 11 (2): 221-35.  Back to cited text no. 145
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 2005; 102 (39): 13944-9.  Back to cited text no. 146
Singh R, Saini N. Downregulation of BCL2 by miRNAs augments drug-induced apoptosis - A combined computational and experimental approach. J Cell Sci 2012; 125(Pt 6): 1568-78.  Back to cited text no. 147
Kuwano Y, Nishida K, Kajita K, Satake Y, Akaike Y, Fujita K, Kano S, Masuda K, Rokutan K. Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3' UTR of BCL2 mRNA. Cell Death Differ 2014; 22 (5): 815-25.  Back to cited text no. 148
Breitschopf K, Haendeler J, Malchow P, Zeiher AM, Dimmeler S. Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol Cell Biol 2000; 20 (5): 1886-96.  Back to cited text no. 149
Niture SK, Jaiswal AK. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem 2012; 287 (13): 9873-86.  Back to cited text no. 150
Niture SK, Jaiswal AK. Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis. J Biol Chem 2011; 286 (52): 44542-56.  Back to cited text no. 151
Kelly PN, Grabow S, Delbridge AR, Strasser A, Adams JM. Endogenous Bcl-xL is essential for Myc-driven lymphomagenesis in mice. Blood 2011; 118 (24): 6380-6.  Back to cited text no. 152
Topp MD, Hartley L, Cook M, Heong V, Boehm E, McShane L, Pyman J, McNally O, Ananda S, Harrell M, Etemadmoghadam D, Galletta L, Alsop K, Mitchell G, Fox SB, Kerr JB, Hutt KJ, Kaufmann SH, Australian Ovarian Cancer Study, Swisher EM, Bowtell DD, Wakefield MJ, Scott CL. Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts. Mol Oncol 2014; 8 (3): 656-68.  Back to cited text no. 153
Gutierrez-Castellanos S, Cruz M, Rabelo L, Godinez R, Reyes-Maldonado E, Riebeling-Navarro C. Differences in BCL-X (L) expression and STAT5 phosphorylation in chronic myeloid leukaemia patients. Eur J Haematol 2004; 72 (4): 231-8.  Back to cited text no. 154
Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, Tatsumi T, Ishida H, Noda T, Nagano H, Doki Y, Mori M, Hayashi N. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol 2010; 52 (5): 698-704.  Back to cited text no. 155
Zhan M, Qu Q, Wang G, Zhou H. Let-7c sensitizes acquired cisplatin-resistant A549 cells by targeting ABCC2 and Bcl-XL. Pharmazie 2013; 68 (12): 955-61.  Back to cited text no. 156
Zhou P, Levy NB, Xie H, Qian L, Lee CY, Gascoyne RD, Craig RW. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood 2001; 97 (12): 3902-9.  Back to cited text no. 157
Hussain SR, Cheney CM, Johnson AJ, Lin TS, Grever MR, Caligiuri MA, Lucas DM, Byrd JC. Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity. Clin Cancer Res 2007; 13 (7): 2144-50.  Back to cited text no. 158
Meng XW, Lee SH, Dai H, Loegering D, Yu C, Flatten K, Schneider P, Dai NT, Kumar SK, Smith BD, Karp JE, Adjei AA, Kaufmann SH. Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43-9006)-induced TRAIL sensitization. J Biol Chem 2007; 282 (41): 29831-46.  Back to cited text no. 159
Ding Q, He X, Xia W, Hsu JM, Chen CT, Li LY, Lee DF, Yang JY, Xie X, Liu JC, Hung MC. Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res 2007; 67 (10): 4564-71.  Back to cited text no. 160
Steele R, Mott JL, Ray RB. MBP-1 upregulates miR-29b that represses Mcl-1, collagens, and matrix-metalloproteinase-2 in prostate cancer cells. Genes Cancer 2010; 1 (4): 381-7.  Back to cited text no. 161
Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, Maecker H, O'Rourke K, Bazan F, Eastham-Anderson J, Yue P, Dornan D, Huang DC, Dixit VM. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 2010; 463 (7277): 103-7.  Back to cited text no. 162
Gong J, Zhang JP, Li B, Zeng C, You K, Chen MX, Yuan Y, Zhuang SM. MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene 2013; 32 (25): 3071-9.  Back to cited text no. 163
Crawford M, Batte K, Yu L, Wu X, Nuovo GJ, Marsh CB, Otterson GA, Nana-Sinkam SP. MicroRNA 133B targets pro-survival molecules MCL-1 and BCL2L2 in lung cancer. Biochem Biophys Res Commun 2009; 388 (3): 483-9.  Back to cited text no. 164
Beverly LJ, Varmus HE. MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family. Oncogene 2009; 28 (9): 1274-9.  Back to cited text no. 165
Gibson L, Holmgreen SP, Huang DC, Bernard O, Copeland NG, Jenkins NA, Sutherland GR, Baker E, Adams JM, Cory S. bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene 1996; 13 (4): 665-75.  Back to cited text no. 166
Merino D, Khaw SL, Glaser SP, Anderson DJ, Belmont LD, Wong C, Yue P, Robati M, Phipson B, Fairlie WD, Lee EF, Campbell KJ, Vandenberg CJ, Cory S, Roberts AW, Ludlam MJ, Huang DC, Bouillet P. Bcl-2, Bcl-x (L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood 2012; 119 (24): 5807-16.  Back to cited text no. 167
Bae IH, Park MJ, Yoon SH, Kang SW, Lee SS, Choi KM, Um HD. Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1. Cancer Res 2006; 66 (10): 4991-5.  Back to cited text no. 168
Bae IH, Yoon SH, Lee SB, Park JK, Ho JN, Um HD. Signaling components involved in Bcl-w-induced migration of gastric cancer cells. Cancer Lett 2009; 277 (1): 22-8.  Back to cited text no. 169
Han S, Hong S, Mo J, Lee D, Choi E, Choi JS, Sun W, Lee HW, Kim H. Impaired extinction of learned contextual fear memory in early growth response 1 knockout mice. Mol Cells 2014; 37 (1): 24-30.  Back to cited text no. 170
Bae IH, Lee WS, Yun DH, Han YH, Lee JS. 3-Hydroxy-3',4'- dimethoxyflavone suppresses Bcl-w-induced invasive potentials and stemness in glioblastoma multiforme. Biochem Biophys Res Commun 2014; 450 (1): 704-10.  Back to cited text no. 171
Lapham A, Adams JE, Paterson A, Lee M, Brimmell M, Packham G. The Bcl-w promoter is activated by beta-catenin/TCF4 in human colorectal carcinoma cells. Gene 2009; 432 (1-2): 112-7.  Back to cited text no. 172
Yasui K, Mihara S, Zhao C, Okamoto H, Saito-Ohara F, Tomida A, Funato T, Yokomizo A, Naito S, Imoto I, Tsuruo T, Inazawa J. Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res 2004; 64 (4): 1403-10.  Back to cited text no. 173
Valdez BC, Murray D, Ramdas L, de Lima M, Jones R, Kornblau S, Betancourt D, Li Y, Champlin RE, Andersson BS. Altered gene expression in busulfan-resistant human myeloid leukemia. Leuk Res 2008; 32 (11): 1684-97.  Back to cited text no. 174
Cao J, Cai J, Huang D, Han Q, Yang Q, Li T, Ding H, Wang Z. miR-335 represents an invasion suppressor gene in ovarian cancer by targeting Bcl-w. Oncol Rep 2013; 30 (2): 701-6.  Back to cited text no. 175
Xu Y, Zhao F, Wang Z, Song Y, Luo Y, Zhang X, Jiang L, Sun Z, Miao Z, Xu H. MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. Oncogene 2012; 31 (11): 1398-407.  Back to cited text no. 176
Lin EY, Orlofsky A, Berger MS, Prystowsky MB. Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J Immunol 1993; 151 (4): 1979-88.  Back to cited text no. 177
Vogler M. BCL2A1: the underdog in the BCL2 family. Cell Death Differ 2012; 19 (1): 67-74.  Back to cited text no. 178
Ottina E, Tischner D, Herold MJ, Villunger A. A1/Bfl-1 in leukocyte development and cell death. Exp Cell Res 2012; 318 (11): 1291-303.  Back to cited text no. 179
Hind CK, Carter MJ, Harris CL, Chan C, James S, Cragg MS. The role of the pro-survival molecule Bfl-1 in melanoma. Int J Biochem Cell Biol 2014; 59: 94-102.  Back to cited text no. 180
Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes Dev 1999; 13 (4): 382-7.  Back to cited text no. 181
Morgan RK, Kingham PJ, Walsh MT, Curran DR, Durcan N, McLean WG, Costello RW. Eosinophil adhesion to cholinergic IMR-32 cells protects against induced neuronal apoptosis. J Immunol 2004; 173 (10): 5963-70.  Back to cited text no. 182
Herold MJ, Zeitz J, Pelzer C, Kraus C, Peters A, Wohlleben G, Berberich I. The stability and anti-apoptotic function of A1 are controlled by its C terminus. J Biol Chem 2006; 281 (19): 13663-71.  Back to cited text no. 183
Kucharczak JF, Simmons MJ, Duckett CS, Gelinas C. Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor. Cell Death Differ 2005; 12 (9): 1225-39.  Back to cited text no. 184
Cluzeau T, Robert G, Mounier N, Karsenti JM, Dufies M, Puissant A, Jacquel A, Renneville A, Preudhomme C, Cassuto JP, Raynaud S, Luciano F, Auberger P. BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients. Oncotarget 2012; 3 (4): 490-501.  Back to cited text no. 185
van de Kooij B, Rooswinkel RW, Kok F, Herrebout M, de Vries E, Paauwe M, Janssen GM, van Veelen PA, Borst J. Polyubiquitination and proteasomal turnover controls the anti-apoptotic activity of Bcl-B. Oncogene 2013; 32 (48): 5439-48.  Back to cited text no. 186
Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 2002; 9 (5): 505-12.  Back to cited text no. 187
Li R, Moudgil T, Ross HJ, Hu HM. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ 2005; 12 (3): 292-303.  Back to cited text no. 188
Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3 (3): 287-96.  Back to cited text no. 189
Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001; 293 (5536): 1829-32.  Back to cited text no. 190
Bean GR, Ganesan YT, Dong Y, Takeda S, Liu H, Chan PM, Huang Y, Chodosh LA, Zambetti GP, Hsieh JJ, Cheng EH. PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci Signal 2013; 6 (268): ra20.  Back to cited text no. 191
Du H, Wolf J, Schafer B, Moldoveanu T, Chipuk JE, Kuwana T. BH3 domains other than Bim and Bid can directly activate Bax/Bak. J Biol Chem 2011; 286 (1): 491-501.  Back to cited text no. 192
Ren D, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 2010; 330 (6009): 1390-3.  Back to cited text no. 193
Vela L, Gonzalo O, Naval J, Marzo I. Direct interaction of Bax and Bak proteins with Bcl-2 homology domain 3 (BH3)-only proteins in living cells revealed by fluorescence complementation. J Biol Chem 2013; 288 (7): 4935-46.  Back to cited text no. 194
Hockings C, Anwari K, Ninnis RL, Brouwer J, O'Hely M, Evangelista M, Hinds MG, Czabotar PE, Lee EF, Fairlie WD, Dewson G, Kluck RM. Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax. Cell Death Dis 2015; 6: e1735.  Back to cited text no. 195
Sarosiek KA, Chi X, Bachman JA, Sims JJ, Montero J, Patel L, Flanagan A, Andrews DW, Sorger P, Letai A. BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol Cell 2013; 51 (6): 751-65.  Back to cited text no. 196
Smith AJ, Dai H, Correia C, Takahashi R, Lee SH, Schmitz I, Kaufmann SH. Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. J Biol Chem 2011; 286 (20): 17682-92.  Back to cited text no. 197
Correia C, Schneider PA, Dai H, Dogan A, Maurer MJ, Church AK, Novak AJ, Feldman AL, Wu X, Ding H, Meng XW, Cerhan JR, Slager SL, Macon WR, Habermann TM, Karp JE, Gore SD, Kay NE, Jelinek DF, Witzig TE, Nowakowski GS, Kaufmann SH. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood 2015; 125 (4): 658-67.  Back to cited text no. 198
Doerflinger M, Glab JA, Puthalakath H. BH3-only proteins: a 20-year stock-take. FEBS J 2015; 282 (6): 1006-16.  Back to cited text no. 199
Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X (L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene 2001; 20 (33): 4507-18.  Back to cited text no. 200
Collins NL, Reginato MJ, Paulus JK, Sgroi DC, Labaer J, Brugge JS. G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. Mol Cell Biol 2005; 25 (12): 5282-91.  Back to cited text no. 201
Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP, Korsmeyer SJ. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003; 424 (6951): 952-6.  Back to cited text no. 202
Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ, Datta SR, Pitter KL, Bird GH, Wikstrom JD, Deeney JT, Robertson K, Morash J, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB, Korsmeyer SJ. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nature Med 2008; 14 (2): 144-53.  Back to cited text no. 203
Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH, Osundiji MA, Matschinsky FM, Walensky LD, Danial NN. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol 2014; 21 (1): 36-42.  Back to cited text no. 204
Yan J, Xiang J, Lin Y, Ma J, Zhang J, Zhang H, Sun J, Danial NN, Liu J, Lin A. Inactivation of BAD by IKK inhibits TNFalpha-induced apoptosis independently of NF-kappaB activation. Cell 2013; 152 (1-2): 304-15.  Back to cited text no. 205
Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40 (2): 280-93.  Back to cited text no. 206
He C, Wei Y, Sun K, Li B, Dong X, Zou Z, Liu Y, Kinch LN, Khan S, Sinha S, Xavier RJ, Grishin NV, Xiao G, Eskelinen EL, Scherer PE, Whistler JL, Levine B. Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 2013; 154 (5): 1085-99.  Back to cited text no. 207
Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, Geneste O, Kroemer G. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X (L). Autophagy 2007; 3 (4): 374-6.  Back to cited text no. 208
Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, Tasdemir E, Pierron G, Troulinaki K, Tavernarakis N, Hickman JA, Geneste O, Kroemer G. Functional and physical interaction between Bcl-X (L) and a BH3-like domain in Beclin-1. EMBO J 2007; 26 (10): 2527-39.  Back to cited text no. 209
Elgendy M, Sheridan C, Brumatti G, Martin SJ. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol Cell 2011; 42 (1): 23-35.  Back to cited text no. 210
Lindqvist LM, Heinlein M, Huang DC, Vaux DL. Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak. Proc Natl Acad Sci U S A 2014; 111 (23): 8512-7.  Back to cited text no. 211
Kamer I, Sarig R, Zaltsman Y, Niv H, Oberkovitz G, Regev L, Haimovich G, Lerenthal Y, Marcellus RC, Gross A. Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 2005; 122 (4): 593-603.  Back to cited text no. 212
Liu Y, Bertram CC, Shi Q, Zinkel SS. Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ 2011; 18 (5): 841-52.  Back to cited text no. 213
Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ. A role for proapoptotic BID in the DNA-damage response. Cell 2005; 122 (4): 579-91.  Back to cited text no. 214
Kaufmann T, Tai L, Ekert PG, Huang DC, Norris F, Lindemann RK, Johnstone RW, Dixit VM, Strasser A. The BH3-only protein bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 2007; 129 (2): 423-33.  Back to cited text no. 215
Zinkel SS, Hurov KE, Gross A. Bid plays a role in the DNA damage response. Cell 2007; 130 (1): 9-10.  Back to cited text no. 216
Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007; 129 (7): 1337-49.  Back to cited text no. 217
Wali JA, Rondas D, McKenzie MD, Zhao Y, Elkerbout L, Fynch S, Gurzov EN, Akira S, Mathieu C, Kay TW, Overbergh L, Strasser A, Thomas HE. The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity. Cell Death Dis 2014; 5: e1124.  Back to cited text no. 218
Rodriguez DA, Zamorano S, Lisbona F, Rojas-Rivera D, Urra H, Cubillos-Ruiz JR, Armisen R, Henriquez DR, Cheng EH, Letek M, Vaisar T, Irrazabal T, Gonzalez-Billault C, Letai A, Pimentel-Muiños FX, Kroemer G, Hetz C. BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1alpha. EMBO J 2012; 31 (10): 2322-35.  Back to cited text no. 219


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