Bcl-2

B-cell CLL/lymphoma 2
PDB rendering based on 1GJH,1G5M.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1G5M​, 1GJH​, 1YSW​, 2O21​, 2O22​, 2O2F​, 2W3L​, 2XA0​, 4AQ3​, 4IEH​, 4LVT​, 4LXD​, 4MAN​
Identifiers
Symbols	BCL2 ; Bcl-2; PPP1R50
External IDs	OMIM: 151430 MGI: 88138 HomoloGene: 527 ChEMBL: 4860 GeneCards: BCL2 Gene
Gene ontology Molecular function • protease binding • protein binding • transcription factor binding • channel activity • channel inhibitor activity • ubiquitin protein ligase binding • identical protein binding • protein homodimerization activity • sequence-specific DNA binding • protein heterodimerization activity • BH3 domain binding • protein phosphatase 2A binding Cellular component • nucleus • cytoplasm • mitochondrion • mitochondrial outer membrane • endoplasmic reticulum • endoplasmic reticulum membrane • cytosol • membrane • nuclear membrane • myelin sheath • pore complex Biological process • protein polyubiquitination • ossification • ovarian follicle development • metanephros development • branching involved in ureteric bud morphogenesis • behavioral fear response • B cell homeostasis • release of cytochrome c from mitochondria • regulation of cell-matrix adhesion • lymphoid progenitor cell differentiation • B cell lineage commitment • response to ischemia • renal system process • protein dephosphorylation • melanin metabolic process • regulation of nitrogen utilization • apoptotic process • humoral immune response • cellular response to DNA damage stimulus • actin filament organization • axonogenesis • female pregnancy • cell aging • male gonad development • extrinsic apoptotic signaling pathway via death domain receptors • intrinsic apoptotic signaling pathway in response to DNA damage • intrinsic apoptotic signaling pathway in response to oxidative stress • response to radiation • response to toxic substance • post-embryonic development • response to iron ion • response to UV-B • response to gamma radiation • regulation of gene expression • negative regulation of autophagy • negative regulation of calcium ion transport into cytosol • regulation of glycoprotein biosynthetic process • programmed cell death • mesenchymal cell development • positive regulation of neuron maturation • positive regulation of smooth muscle cell migration • cell growth • peptidyl-serine phosphorylation • peptidyl-threonine phosphorylation • cochlear nucleus development • gland morphogenesis • regulation of transmembrane transporter activity • negative regulation of ossification • positive regulation of cell growth • negative regulation of cell growth • melanocyte differentiation • negative regulation of cell migration • positive regulation of B cell proliferation • hair follicle morphogenesis • axon regeneration • regulation of protein stability • endoplasmic reticulum calcium ion homeostasis • glomerulus development • negative regulation of cellular pH reduction • negative regulation of myeloid cell apoptotic process • T cell differentiation in thymus • positive regulation of peptidyl-serine phosphorylation • negative regulation of osteoblast proliferation • response to cytokine • response to nicotine • organ growth • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • positive regulation of multicellular organism growth • B cell proliferation • cellular response to glucose starvation • response to drug • response to hydrogen peroxide • T cell homeostasis • negative regulation of apoptotic process • positive regulation of catalytic activity • CD8-positive, alpha-beta T cell lineage commitment • regulation of protein homodimerization activity • regulation of protein heterodimerization activity • negative regulation of neuron apoptotic process • ear development • regulation of viral genome replication • innate immune response • positive regulation of melanocyte differentiation • negative regulation of retinal cell programmed cell death • regulation of mitochondrial membrane permeability • focal adhesion assembly • spleen development • thymus development • digestive tract morphogenesis • oocyte development • positive regulation of skeletal muscle fiber development • pigment granule organization • homeostasis of number of cells within a tissue • B cell receptor signaling pathway • response to glucocorticoid • neuron apoptotic process • defense response to virus • regulation of mitochondrial membrane potential • negative regulation of mitochondrial depolarization • regulation of calcium ion transport • transmembrane transport • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • cellular response to organic substance • cellular response to hypoxia • reactive oxygen species metabolic process • extrinsic apoptotic signaling pathway in absence of ligand • intrinsic apoptotic signaling pathway • positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway • negative regulation of G1/S transition of mitotic cell cycle • negative regulation of reactive oxygen species metabolic process • negative regulation of anoikis • negative regulation of apoptotic signaling pathway • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand • negative regulation of intrinsic apoptotic signaling pathway • positive regulation of intrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	596	12043
Ensembl	ENSG00000171791	ENSMUSG00000057329
UniProt	P10415	P10417
RefSeq (mRNA)	NM_000633	NM_009741
RefSeq (protein)	NP_000624	NP_033871
Location (UCSC)	Chr 18: 63.12 – 63.32 Mb	Chr 1: 106.54 – 106.71 Mb
PubMed search

Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis.^[1][2] Bcl-2 is specifically considered an important anti-apoptotic protein and is thus classified as an oncogene.

Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas. Orthologs^[3] (such as Bcl2 in mice) have been identified in numerous mammals for which complete genome data are available.

Like BCL3, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.

Isoforms

The two isoforms of Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also known as 1G5O/1GJH, exhibit a similar fold. However, results in the ability of these isoforms to bind to the BAD and BAK proteins, as well as in the structural topology and electrostatic potential of the binding groove, suggest differences in antiapoptotic activity for the two isoforms ^[4]

Normal physiological function

BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. The pro-apoptotic proteins in the BCL-2 family, including Bax and Bak, normally act on the mitochondrial membrane to promote permeabilization and release of cytochrome C and ROS, that are important signals in the apotosis cascade. These pro-apoptotic proteins are in turn activated by BH3-only proteins, and are inhibited by the function of BCL-2 and its relative BCL-Xl.^[5]

There are additional non-canonical roles of BCL-2 that are being explored. BLC-2 is known to regulate mitochondrial dynamics, and is involved in the regulation of mitochondrial fusion and fission. Additionally, in pancreatic beta-cells, BCL-2 and BCL-Xl are known to be involved in controlling metabolic activity and insulin secretion, with inhibition of BCL-2/Xl showing increasing metabolic activity, but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.

Role in disease

Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.

Cancer

Cancer can be seen as a disturbance in the homeostatic balance between cell growth and cell death. Over-expression of anti-apoptotic genes, and under-expression of pro-apoptotic genes, can result in the lack of cell death that is characteristic of cancer. An example can be seen in lymphomas. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone does not cause cancer. But simultaneous over-expression of Bcl-2 and the proto-oncogene myc may produce aggressive B-cell malignancies including lymphoma.^[6] In follicular lymphoma, a chromosomal translocation commonly occurs between the fourteenth and the eighteenth chromosomes — t(14;18) — which places the Bcl-2 gene from chromosome 18 next to the immunoglobulin heavy chain locus on chromosome 14. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.^[7] This decreases the propensity of these cells for apoptosis.

Auto-immune diseases

Apoptosis plays an active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens via both central and peripheral tolerance. In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.^[8] The autoimmune disease type 1 diabetes can be caused by defective apoptosis, which leads to aberrant T cell AICD and defective peripheral tolerance. Due to the fact that dendritic cells are the immune system's most important antigen-presenting cells, their activity must be tightly regulated by mechanisms such as apoptosis. Researchers have found that mice containing dendritic cells that are Bim -/-, thus unable to induce effective apoptosis, suffer autoimmune diseases more so than those that have normal dendritic cells.^[8] Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.^[8]

Other

Apoptosis plays an important role in regulating a variety of diseases. For example, schizophrenia is a neurodegenerative disease that may result from an abnormal ratio of pro- and anti-apoptotic factors.^[9] Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of caspase-3.^[9]

Diagnostic use

Antibodies to Bcl-2 can be used with immunohistochemistry to identify cells containing the antigen. In healthy tissue, these antibodies react with B-cells in the mantle zone, as well as some T-cells. However, positive cells increase considerably in follicular lymphoma, as well as many other forms of cancer. In some cases, the presence or absence of Bcl-2 staining in biopsies may be significant for the patient's prognosis or likelihood of relapse.^[10]

Targeted therapies

Bcl-2 inhibitors (many are BH3-mimetics) include :

Genasense

An antisense oligonucleotide drug Genasense (G3139) was developed by Genta Incorporated to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA that hybridises with and inactivates mRNA, preventing the protein from being formed.

Human lymphoma cell proliferation (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.^[11]

These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.^[12] As of 2016, the drug had not been approved and its developer was out of business.^[13]

ABT-737 and ABT-263

In the mid-2000s, Abbott Laboratories developed a novel inhibitor of Bcl-2, Bcl-xL and Bcl-w, known as ABT-737. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI) that target these Bcl-2 family proteins, but not A1 or Mcl-1. ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. In vitro studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.^[14] ABT-737 does not directly induce apoptosis; it enhances the effects of apoptotic signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines.

In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.^[15] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.^[16] Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its derivative ABT-263 has similar activity on small cell lung cancer (SCLC) cell lines and has entered clinical trials.^[17]

Venetoclax

Clinical trials studied the effects of venetoclax (ABT-199), a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia (CLL).^[18] Good responses have been reported.^[19] A phase 3 trial started in Dec 2015.^[20] It was approved by the US FDA in April 2016 for CLL associated with 17-p deletion.^[21] This is the first FDA approval of a BCL-2 inhibitor.^[21]

Others

• Obatoclax (GX15-070) has phase II results for small-cell lung cancer.^[22]
• Mito-prime is a technique for increasing the sensitivity to the inhibition of Bcl-2 function by BH3-mimetics. It is proposed for use as a technique for rapidly identifying novel BH3-mimetics for assessing their potency and specificity.^[23]

Interactions

Overview of signal transduction pathways involved in apoptosis.

Bcl-2 has been shown to interact with:

• BAK1,^[24][25]
• BCAP31,^[26]
• BCL2-like 1,^[24][27]
• BCL2L11,^[28][29][30]
• BECN1,^[31]
• BID,^[28][32]
• BMF,^[33]
• BNIP2,^[34][35]
• BNIP3,^[35][36]
• BNIPL,^[34][37]
• BAD^[28][38]
• BAX,^{[24][39][40][41]}
• BIK,^[28][42]
• C-Raf,^[43]
• CAPN2,^[44]
• CASP8,^[45][46]
• Cdk1,^[47][48]
• HRK,^[28][49]
• IRS1,^[50]
• Myc,^[51]
• NR4A1,^[24]
• Noxa,^[28][52]
• PPP2CA,^[53]
• PSEN1,^[54]
• RAD9A,^[39]
• RRAS,^[55]
• RTN4,^[56]
• SMN1,^[57]
• SOD1,^[58] and
• TP53BP2.^[59]

Human BCL-2 genes

BAK; BAK1; BAX; BCL2; BCL2A1; BCL2L1; BCL2L10; BCL2L13; BCL2L14; BCL2L2; BCL2L7P1; BOK; MCL1; LGALS7 (Galectin-7)

See also

• Apoptosis
• Apoptosome
• Bcl-2 homologous antagonist killer (BAK)
• Bcl-2-associated X protein (BAX)
• Bcl-xL
• BH3 interacting domain death agonist (BID)
• Caspases
• Cytochrome c
• Noxa
• Mcl-1
• Mitochondrion
• Microphthalmia-associated transcription factor
• Protein mimetic
• p53 upregulated modulator of apoptosis (PUMA)

References

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External links

• The Bcl-2 Family Database
• The Bcl-2 Family at celldeath.de
• Bcl-2 publications sorted by impact at caspases.org
• bcl-2 Genes at the US National Library of Medicine Medical Subject Headings (MeSH)
• c-bcl-2 Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)