Wikipedia

Bcl-2

Bcl-2,encoded in humans by theBCL2gene,is the founding member of theBcl-2 familyofregulator proteins.BCL2 blocks programmed cell death (apoptosis)[5]while other BCL2 family members can either inhibit or induce it.[6][7]It was the first apoptosis regulator identified in any organism.[8]

BCL2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesBCL2,Bcl-2, PPP1R50, B-cell CLL/lymphoma 2, apoptosis regulator, BCL2 apoptosis regulator, Genes, bcl-2
External IDsOMIM:151430;MGI:88138;HomoloGene:527;GeneCards:BCL2;OMA:BCL2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

596

12043

Ensembl

ENSG00000171791

ENSMUSG00000057329

UniProt

P10415

P10417

RefSeq (mRNA)

NM_000633
NM_000657

NM_009741
NM_177410

RefSeq (protein)

NP_000624
NP_000648

NP_033871
NP_803129

Location (UCSC)Chr 18: 63.12 – 63.32 MbChr 1: 106.47 – 106.64 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Bcl-2 derives its name fromB-cell lymphoma 2,as it is the second member of a range of proteins initially described inchromosomal translocationsinvolvingchromosomes14and18infollicular lymphomas.Orthologs[9](such asBcl2in mice) have been identified in numerousmammalsfor which completegenomedata are available.

LikeBCL3,BCL5,BCL6,BCL7A,BCL9,andBCL10,it has clinical significance inlymphoma.

Isoforms

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The twoisoformsof Bcl-2, Isoform 1, and Isoform 2, exhibit a similar fold. However, results in the ability of these isoforms to bind to theBADandBAKproteins, as well as in the structural topology andelectrostatic potentialof the binding groove, suggest differences in antiapoptotic activity for the twoisoforms.[10]

Function

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BCL-2 is localized to the outer membrane ofmitochondria,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, includingBaxandBak,normally act on the mitochondrial membrane to promote permeabilization and release ofcytochrome candROS,that are important signals in the apoptosis cascade. These pro-apoptotic proteins are in turn activated by BH3-only proteins, and are inhibited by the function of BCL-2 and its relativeBCL-Xl.[11]

There are additional non-canonical roles of BCL-2 that are being explored. BCL-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,[12]but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.[13]

Role in disease

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See also:Apoptosis implication in disease

Damage to the Bcl-2 gene has been identified as a cause of a number ofcancers,includingmelanoma,breast,prostate,chronic lymphocytic leukemia,andlung cancer,and a possible cause ofschizophreniaandautoimmunity.It is also a cause of resistance to cancer treatments.[14]

Cancer

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Cancer can be seen as a disturbance in thehomeostaticbalance 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 inlymphomas.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-oncogenemycmay produce aggressiveB-cellmalignancies including lymphoma.[15]Infollicular lymphoma,achromosomal translocationcommonly occurs between the fourteenth and the eighteenthchromosomes– t(14;18) – which places the Bcl-2 gene from chromosome 18 next to theimmunoglobulinheavy chain locus on chromosome 14. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.[16]This decreases the propensity of these cells for apoptosis. Bcl-2 expression is frequent insmall cell lung cancer,accounting for 76% cases in one study.[17]

Auto-immune diseases

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Apoptosisplays an active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigensvia both central and peripheral tolerance. In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.[18]The autoimmune diseasetype 1 diabetescan be caused by defective apoptosis, which leads to aberrant T cellAICDand defective peripheral tolerance. Due to the fact thatdendritic cellsare the immune system's most importantantigen-presenting cells,their activity must be tightly regulated by mechanisms such as apoptosis. Researchers have found that mice containing dendritic cells that areBim-/-, thus unable to induce effective apoptosis, haveautoimmune diseasesmore so than those that have normal dendritic cells.[18]Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.[18]

Other

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Apoptosis plays an important role in regulating a variety of diseases. For example, schizophrenia is a psychiatric disorder in which an abnormal ratio of pro- and anti-apoptotic factors may contribute towards pathogenesis.[19]Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression ofcaspase-3.[19]

Diagnostic use

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Antibodies to Bcl-2 can be used withimmunohistochemistryto identify cells containing the antigen. In healthy tissue, these antibodies react with B-cells in themantle zone,as well as someT-cells.However, positive cells increase considerably infollicular lymphoma,as well as many other forms of cancer. In some cases, the presence or absence of Bcl-2 staining inbiopsiesmay be significant for the patient'sprognosisor likelihood ofrelapse.[20]

Targeted therapies

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Targeted and selective Bcl-2 inhibitors that have been in development or are currently in the clinic include:

Oblimersen

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An antisenseoligonucleotidedrug,oblimersen(G3139), was developed byGenta Incorporatedto target Bcl-2. AnantisenseDNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). Anantisense drugis a short sequence of modified DNA that hybridises with and inactivates mRNA, preventing theproteinfrom being formed.[citation needed]

Humanlymphomacellproliferation (with t(14;18) translocation) could be inhibited byantisense oligonucleotidetargeted at the startcodonregion of Bcl-2mRNA.In vitrostudies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.[21]

These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.[22]As of 2016, the drug had not been approved and its developer was out of business.[23]

ABT-737 and navitoclax (ABT-263)

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In the mid-2000s,Abbott Laboratoriesdeveloped a novel inhibitor of Bcl-2,Bcl-xLand Bcl-w, known asABT-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 orMcl-1.ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w.In vitrostudies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.[24]

In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.[25]In preclinical studies utilizingpatient xenografts,ABT-737 showed efficacy for treating lymphoma and other blood cancers.[26]Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its orallybioavailablederivativenavitoclax(ABT-263) has similar activity onsmall cell lung cancer(SCLC) cell lines and has entered clinical trials.[27]While clinical responses with navitoclax were promising, mechanistic dose-limitingthrombocytopeniawas observed in patients under treatment due to Bcl-xL inhibition inplatelets.[28][29][30]

Venetoclax (ABT-199)

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Due to dose-limiting thrombocytopenia of navitoclax as a result of Bcl-xL inhibition,Abbviesuccessfully developed the highly selective inhibitorvenetoclax(ABT-199), which inhibits Bcl-2, but not Bcl-xL or Bcl-w.[31]Clinical trials studied the effects of venetoclax, a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients withchronic lymphocytic leukemia(CLL).[32][33]Good responses have been reported and thrombocytopenia was no longer observed.[33][34]A phase 3 trial started in Dec 2015.[35] It was approved by theUS FDAin April 2016 as a second-line treatment for CLL associated with 17-p deletion.[36]This was the first FDA approval of a BCL-2 inhibitor.[36]In June 2018, the FDA broadened the approval for anyone with CLL or small lymphocytic lymphoma, with or without 17p deletion, still as a second-line treatment.[37]

Sonrotoclax (BGB-11417)

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Venetoclax drug resistance has been noted with the G101V mutation in BCL-2 observed in relapsing patients.[38]Sonrotoclaxshows greater tumor growth inhibition in hematologic tumor models than venetoclax and inhibits venetoclax-resistant BCL-2 variants. Sonrotoclax is under clinical investigation as a monotherapy and in combination with other anticancer agents.[39]

Interactions

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Overview of signal transduction pathways involved inapoptosis

Bcl-2 has been shown tointeractwith:

See also

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References

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