The Bcl-2 family of proteins plays a central role in regulating apoptosis, acting at the mitochondria to promote or inhibit cell death. This family is composed of both pro-apoptotic and anti-apoptotic members, which interact through a complex network of interactions to determine the fate of the cell. The balance between these opposing forces is critical for maintaining cellular health and homeostasis, and dysregulation of these proteins can lead to diseases such as cancer, neurodegenerative disorders, and autoimmune diseases
The Bcl-2 family can be broadly classified into three main subgroups based on their structure and function: the anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL, Mcl-1), the pro-apoptotic effectors (e.g., Bax, Bak), and the pro-apoptotic BH3-only proteins (e.g., Bid, Bad, Bim, Noxa, Puma). The anti-apoptotic proteins work by binding to and sequestering the pro-apoptotic members, preventing them from inducing mitochondrial outer membrane permeabilization (MOMP), which is a critical step in the initiation of apoptosis. MOMP results in the release of cytochrome c and other apoptogenic factors from the mitochondria into the cytoplasm, where they activate the caspase cascade that leads to cell death.
The Bcl-2 family can be broadly classified into three main subgroups based on their structure and function: the anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL, Mcl-1), the pro-apoptotic effectors (e.g., Bax, Bak), and the pro-apoptotic BH3-only proteins (e.g., Bid, Bad, Bim, Noxa, Puma). The anti-apoptotic proteins work by binding to and sequestering the pro-apoptotic members, preventing them from inducing mitochondrial outer membrane permeabilization (MOMP), which is a critical step in the initiation of apoptosis. MOMP results in the release of cytochrome c and other apoptogenic factors from the mitochondria into the cytoplasm, where they activate the caspase cascade that leads to cell death.
The pro-apoptotic effectors, Bax and Bak, are crucial for the permeabilization of the mitochondrial membrane. In response to apoptotic signals, these proteins undergo conformational changes and oligomerize to form pores in the mitochondrial membrane, facilitating the release of cytochrome c. The BH3-only proteins act as sentinels that respond to cellular stress signals, such as DNA damage, growth factor deprivation, or oxidative stress. They promote apoptosis by either activating Bax and Bak or by inhibiting the anti-apoptotic proteins, thus shifting the balance towards cell death.
The regulation of the Bcl-2 family is intricately linked to many cellular processes and signaling pathways, making it a focal point for therapeutic interventions, particularly in cancer where apoptosis evasion is a hallmark. Drugs that mimic BH3-only proteins (BH3 mimetics), such as Venetoclax, which targets Bcl-2, have been developed to reactivate apoptotic pathways selectively in cancer cells. These treatments hold promise for combating tumors that overexpress anti-apoptotic members of the Bcl-2 family, offering a strategy to tip the balance towards apoptosis in cells that have become adept at surviving traditional therapies.
Figure 1 The Bcl-2 family of apoptotic regulators. (Dewson, 2010)
BAG3, or Bcl-2-associated athanogene 3, is a multifunctional protein that plays a crucial role in various cellular processes, including apoptosis, autophagy, and stress response. It is part of the BAG family of co-chaperones, which regulate the ATPase activity of heat shock proteins (Hsp), particularly Hsp70. This interaction is vital for protein homeostasis and the protective responses of cells under stress conditions. BAG3 is uniquely involved in both promoting cell survival and regulating cell death. Its expression is induced by stressful stimuli such as heat shock, oxidative stress, and heavy metals. In the context of apoptosis, BAG3 can inhibit the apoptotic pathway by interacting with anti-apoptotic Bcl-2 or by modulating the activity of caspases. In autophagy, BAG3 plays a regulatory role by facilitating the degradation of damaged organelles or misfolded proteins, thus promoting cellular survival under stress. The role of BAG3 extends to muscle function and integrity. It is critically involved in the maintenance of the cytoskeleton and the contractile function of muscle cells, making it important in the context of muscular dystrophies and cardiomyopathies. Mutations or dysregulation of BAG3 have been associated with myopathies, where impaired BAG3 function leads to muscle degeneration and weakened muscle strength. In cancer, BAG3 expression is often upregulated and contributes to cancer cell survival, resistance to therapy, and metastasis. Its involvement in multiple survival pathways makes it a potential target for cancer therapy, where inhibiting BAG3 could enhance the efficacy of existing treatments.
BAX, or BCL2-associated X protein, is a pro-apoptotic member of the Bcl-2 protein family, which plays a crucial role in the regulation of apoptosis, primarily through the mitochondrial (intrinsic) pathway. BAX is a central effector in apoptosis, promoting cell death by facilitating the release of cytochrome c and other pro-apoptotic factors from the mitochondria into the cytosol, a key step in the activation of downstream caspases that execute cell death. Under normal conditions, BAX is located in the cytosol in an inactive form. In response to apoptotic stimuli, such as DNA damage, oxidative stress, or growth factor deprivation, BAX undergoes a conformational change and translocates to the mitochondrial membrane. Once at the membrane, BAX oligomerizes and inserts into the mitochondrial outer membrane to form pores, leading to the release of cytochrome c. This process is tightly regulated by interactions with other Bcl-2 family members; anti-apoptotic proteins such as Bcl-2 and Bcl-xL inhibit BAX activation, while other pro-apoptotic proteins like BID or PUMA facilitate its activation and translocation. The activity of BAX is essential for maintaining cellular homeostasis by ensuring that damaged or unwanted cells can effectively undergo apoptosis. Dysregulation of BAX function is implicated in a range of diseases. In cancer, decreased BAX expression or function can contribute to apoptosis resistance, allowing cancer cells to survive and proliferate unchecked. Conversely, excessive BAX activity is associated with diseases characterized by excessive cell death, such as neurodegenerative disorders.
MCL1, or Myeloid Cell Leukemia 1, is a critical member of the Bcl-2 family of proteins, which are key regulators of apoptosis. MCL1 is unique among the Bcl-2 family due to its dual role in both promoting cell survival and contributing to the apoptotic process, depending on its isoform and cellular context. The protein functions primarily as an anti-apoptotic factor by sequestering pro-apoptotic proteins such as BAK and BAX, thereby preventing them from initiating the mitochondrial pathway of apoptosis. MCL1 is essential for the survival of a variety of cell types, including hematopoietic cells, and plays a pivotal role in development and maintaining tissue homeostasis. Its expression is tightly regulated at both transcriptional and post-translational levels, and its rapid turnover rate allows cells to swiftly respond to survival or death signals. This dynamic regulation is critical during situations like embryonic development, immune response, and tissue repair. The overexpression of MCL1 has been linked to a number of cancers, where it contributes to the survival of cancer cells and resistance to chemotherapy. Because MCL1 helps cancer cells evade apoptosis, it has become a significant target for cancer therapy. Inhibitors of MCL1 are currently under development and clinical trials, aiming to reduce tumor resistance to apoptosis and enhance the efficacy of existing cancer treatments. Moreover, dysregulation of MCL1 is also implicated in several non-cancerous diseases, including autoimmune disorders and cardiovascular diseases, where improper apoptosis contributes to disease pathology.
Biomarker | Alternative Names | Gene ID | UniProt ID | Roles |
BAG2 | BAG-2; dJ417I1.2 | 9532 | O95816 | BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The predicted BAG2 protein contains 211 amino acids. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. |
BAG3 | BCL2 Associated Athanogene 3; Bcl-2-Binding Protein Bis; Docking Protein CAIR-1; BAG-3; BIS; BAG Family Molecular Chaperone Regulator 3 | 9531 | O95817 | BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. |
BAK1 | BCL2 Antagonist/Killer 1; Apoptosis Regulator BAK; Bcl-2-Like Protein 7; Bcl2-L-7; BCL2L7; CDN1; BAK | 578 | Q16611 | The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress. |
BAX | BCL2L4 | 581 | Q07812 | The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. The association and the ratio of BAX to BCL2 also determines survival or death of a cell following an apoptotic stimulus. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. Multiple alternatively spliced transcript variants, which encode different isoforms, have been reported for this gene. |
BCKDK | Branched Chain Ketoacid Dehydrogenase Kinase; BCKD-Kinase; EC 2.7.11.4; BCKDHKIN; [3-Methyl-2-Oxobutanoate Dehydrogenase [Lipoamide]] Kinase, Mitochondrial; 3-Methyl-2-Oxobutanoate Dehydrogenase [Lipoamide] Kinase, Mitochondrial | 29603 | Q00972 | The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. |
BCL10 | B Cell CLL/Lymphoma 10; CED-3/ICH-1 Prodomain Homologous E10-Like Regulator; Mammalian CARD-Containing Adapter Molecule E10; CARD-Containing Molecule Enhancing NF-Kappa-B; Caspase-Recruiting Domain-Containing Protein; CARD-Containing Apoptotic Signaling Protein; CARD Containing Molecule Enhancing NF-KB; CARD-Containing Proapoptotic Protein; CARD-Like Apoptotic Protein; Cellular Homolog Of VCARMEN; B-Cell CLL/Lymphoma 10; Cellular-E10 | 8915 | O95999 | This gene was identified by its translocation in a case of mucosa-associated lymphoid tissue (MALT) lymphoma. The protein encoded by this gene contains a caspase recruitment domain (CARD), and has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. This protein is found to form a complex with MALT1, a protein encoded by another gene known to be translocated in MALT lymphoma. MALT1 and this protein are thought to synergize in the activation of NF-kappaB, and the deregulation of either of them may contribute to the same pathogenetic process that leads to the malignancy. Alternative splicing results in multiple transcript variants. |
BCL-2 | BCL2, Apoptosis Regulator; Protein Phosphatase 1, Regulatory Subunit 50; B-Cell CLL/Lymphoma 2; Apoptosis Regulator Bcl-2; PPP1R50; Bcl-2 | 596 | P10415 | This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Alternative splicing results in multiple transcript variants. |
BCL2A1 | BCL2 Related Protein A1; Hemopoietic-Specific Early Response Protein; Bcl-2-Like Protein 5; Protein BFL-1; Bcl2-L-5; BCL2L5; HBPA1; BFL1; GRS | 597 | Q16548 | This gene encodes a member of the BCL-2 protein family. The proteins of this family form hetero- or homodimers and act as anti- and pro-apoptotic regulators that are involved in a wide variety of cellular activities such as embryonic development, homeostasis and tumorigenesis. The protein encoded by this gene is able to reduce the release of pro-apoptotic cytochrome c from mitochondria and block caspase activation. This gene is a direct transcription target of NF-kappa B in response to inflammatory mediators, and is up-regulated by different extracellular signals, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), CD40, phorbol ester and inflammatory cytokine TNF and IL-1, which suggests a cytoprotective function that is essential for lymphocyte activation as well as cell survival. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. |
BCL2L12 | BCL2-Like 12 (Proline Rich); Bcl-2-Related Proline-Rich Protein; Bcl2-L-12; BPR | 83596 | Q9HB09 | This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. |
BCL2L2 | BCLW; BCL-W; PPP1R51; BCL2-L-2 | 599 | Q92843 | This gene encodes a member of the BCL-2 protein family. The proteins of this family form hetero- or homodimers and act as anti- and pro-apoptotic regulators. Expression of this gene in cells has been shown to contribute to reduced cell apoptosis under cytotoxic conditions. Studies of the related gene in mice indicated a role in the survival of NGF- and BDNF-dependent neurons. Mutation and knockout studies of the mouse gene demonstrated an essential role in adult spermatogenesis. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream PABPN1 (poly(A) binding protein, nuclear 1) gene. |
Bcl-xL | Bcl-xL | |||
BID | BH3 Interacting Domain Death Agonist; P22 BID; BH3-Interacting Domain Death Agonist; Human BID Coding Sequence; Apoptic Death Agonist; BID Isoform ES(1b) | 637 | P55957 | This gene encodes a death agonist that heterodimerizes with either agonist BAX or antagonist BCL2. The encoded protein is a member of the BCL-2 family of cell death regulators. It is a mediator of mitochondrial damage induced by caspase-8 (CASP8); CASP8 cleaves this encoded protein, and the COOH-terminal part translocates to mitochondria where it triggers cytochrome c release. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. |
BIK | BIK; Human BIK | 638 | Q13323 | |
BNIP3 | BCL2 Interacting Protein 3; BCL2/Adenovirus E1B 19kDa Interacting Protein 3; NIP3; BCL2/Adenovirus E1B 19 KDa Protein-Interacting Protein 3 | 664 | Q12983 | This gene is encodes a mitochondrial protein that contains a BH3 domain and acts as a pro-apoptotic factor. The encoded protein interacts with anti-apoptotic proteins, including the E1B 19 kDa protein and Bcl2. This gene is silenced in tumors by DNA methylation. |
BNIP3L | BCL2 Interacting Protein 3 Like; BCL2/Adenovirus E1B 19 KDa Protein-Interacting Protein 3A; BCL2/Adenovirus E1B 19kDa Interacting Protein 3 Like; NIP3-Like Protein X; BNIP3a; NIP3L; NIX | 665 | O60238 | This gene encodes a protein that belongs to the pro-apoptotic subfamily within the Bcl-2 family of proteins. The encoded protein binds to Bcl-2 and possesses the BH3 domain. The protein directly targets mitochondria and causes apoptotic changes, including loss of membrane potential and the release of cytochrome c. |
DYNLL1 | LC8; PIN; DLC1; DLC8; LC8a; DNCL1; hdlc1; DNCLC1 | 8655 | P63167 | Cytoplasmic dyneins are large enzyme complexes with a molecular mass of about 1,200 kD. They contain two force-producing heads formed primarily from dynein heavy chains, and stalks linking the heads to a basal domain, which contains a varying number of accessory intermediate chains. The complex is involved in intracellular transport and motility. The protein described in this record is a light chain and exists as part of this complex but also physically interacts with and inhibits the activity of neuronal nitric oxide synthase. Binding of this protein destabilizes the neuronal nitric oxide synthase dimer, a conformation necessary for activity, and it may regulate numerous biologic processes through its effects on nitric oxide synthase activity. Alternate transcriptional splice variants have been characterized. |
MASP1 | MASP1; mannan-binding lectin serine peptidase 1 (C4/C2 activating component of Ra-reactive factor); CRARF,mannan binding lectin serine protease 1 (C4/C2 activating component of Ra reactive factor) , PRSS5; mannan-binding lectin serine protease 1; MASP; Complement factor MASP-3; Complement factor MASP3; Complement-activating component of Ra-reactive factor; CRARF; Mannose binding lectin associated serine protease 1; Mannose binding protein associated serine protease; Mannose-binding lectin-associated serine protease 1; Mannose-binding lectin-associated serine protease-1; MASP; PRSS 5; Ra-reactive factor serine protease p100; RaRF; Serine protease 5; serine protease 5; OTTHUMP00000209926; OTTHUMP00000209927; OTTHUMP00000209928; OTTHUMP00000209929; OTTHUMP00000209930; complement factor MASP-3; Ra-reactive factor serine protease p100; mannose-binding protein-associated se; MAP1; RaRF; CRARF; MASP3; MAp44; PRSS5; CRARF1; | 5648 | P48740 | This gene encodes a serine protease that functions as a component of the lectin pathway of complement activation. The complement pathway plays an essential role in the innate and adaptive immune response. The encoded protein is synthesized as a zymogen and is activated when it complexes with the pathogen recognition molecules of lectin pathway, the mannose-binding lectin and the ficolins. This protein is not directly involved in complement activation but may play a role as an amplifier of complement activation by cleaving complement C2 or by activating another complement serine protease, MASP-2. The encoded protein is also able to cleave fibrinogen and factor XIII and may may be involved in coagulation. A splice variant of this gene which lacks the serine protease domain functions as an inhibitor of the complement pathway. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010] |
MCL1 | MCL1, BCL2 Family Apoptosis Regulator; Myeloid Cell Leukemia Sequence 1 (BCL2-Related); Bcl-2-Related Protein EAT/Mcl1; Myeloid Cell Leukemia 1; Bcl-2-Like Protein 3; Bcl2-L-3; Mcl1/EAT; BCL2L3; Induced Myeloid Leukemia Cell Differentiation Protein Mcl-1 | 4170 | Q07820 | This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010] |
MOAP1 | MOAP1; Modulator Of Apoptosis 1; Paraneoplastic Ma Antigen Family Member 4; Paraneoplastic Antigen Ma4; Paraneoplastic Antigen Like 4; MAP1; MAP-1 | 64112 | Q96BY2 | The protein encoded by this gene was identified by its interaction with apoptosis regulator BAX protein. This protein contains a Bcl-2 homology 3 (BH3)-like motif, which is required for the association with BAX. When overexpressed, this gene has been shown to mediate caspase-dependent apoptosis. |
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