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{{Short description|Protein found in humans}}
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{{Infobox_gene}}
'''Bcl-2'''
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 translocation]]s involving [[chromosome]]s [[Chromosome 14|14]] and [[Chromosome 18|18]] in [[follicular lymphoma]]s. [[Orthologs]]<ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: Bcl-2 coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000171791_BCL2.xml | access-date = 20 December 2009 | archive-url = https://web.archive.org/web/20150924061939/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000171791_BCL2.xml | archive-date = 24 September 2015 | url-status = dead }}</ref> (such as ''Bcl2'' in mice) have been identified in numerous [[mammals]] for which complete [[genome]] data are available.
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== Isoforms ==
The two [[isoforms]] of Bcl-2, Isoform 1, and Isoform 2, exhibit a similar fold. However, results in the ability of these isoforms to bind to the [[Bcl-2-associated death promoter|BAD]] and [[Bcl-2 homologous antagonist killer|BAK]] proteins, as well as in the structural topology and [[electrostatic potential]] of the binding groove, suggest differences in antiapoptotic activity for the two [[Protein isoform|isoforms]].<ref name="Human Bcl2 1G5M">{{PDB|1G5M}}; {{cite journal | vauthors = Petros AM, Medek A, Nettesheim DG, Kim DH, Yoon HS, Swift K, Matayoshi ED, Oltersdorf T, Fesik SW | title = Solution structure of the antiapoptotic protein bcl-2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages =
== Function ==
BCL-2 is localized to the outer membrane of [[Mitochondrion|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 [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|Bak]], normally act on the mitochondrial membrane to promote permeabilization and release of [[cytochrome c]] and [[Reactive oxygen species|ROS]], 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 relative [[Bcl-xL|BCL-Xl]].<ref>{{cite journal |
[[File:Bcl2 inhibition of Bax on mitochondrion.png|300px]]
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,<ref>{{cite journal |pmid= 22933114 |doi= 10.2337/db11-1464 |volume=62 |issue=1 |title= Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ß-cells |pmc= 3526034 |year=2013 |journal= Diabetes |vauthors= Luciani DS, White SA, Widenmaier SB, Saran VV, Taghizadeh F, Hu X, Allard MF, Johnson JD |pages= 170–182}}</ref> but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.<ref>{{cite journal |pmid= 27070098 |doi= 10.1210/en.2015-1964 |volume=157 |issue=6 |title= Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ß-Cells |year=2016 |journal= Endocrinology |vauthors= Aharoni-Simon M, Shumiatcher R, Yeung A, Shih AZ, Dolinsky VW, Doucette CA, Luciani DS |pages= 2270–2281|doi-access= free }}</ref>▼
▲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,<ref>{{cite journal |
== Role in disease ==
{{See also|Apoptosis#Implication_in_disease|label 1 = Apoptosis implication in disease}}
Damage to the Bcl-2 gene has been identified as a cause of a number of [[cancer]]s, including [[melanoma]], [[breast cancer|breast]], [[prostate cancer|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.<ref name = pmid30544835>{{cite journal | vauthors =
===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 [[lymphoma]]s. 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.<ref name="pmid17179226">{{cite journal | vauthors = Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ | title = Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA | journal = Blood | volume = 109 | issue = 7 | pages =
===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.<ref name="pmid17162368">{{cite journal | vauthors = Li A, Ojogho O, Escher A | title = Saving death: apoptosis for intervention in transplantation and autoimmunity | journal = Clinical & Developmental Immunology | volume = 13 | issue = 2–4 | pages =
=== Other ===
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.<ref name="pmid16226876">{{cite journal | vauthors = Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF
== 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-cell]]s. 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 [[biopsy|biopsies]] may be significant for the patient's [[prognosis]] or likelihood of [[relapse]].<ref name=Leong>{{cite book
== Targeted therapies ==
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An antisense [[oligonucleotide]] drug, [[oblimersen]] (G3139), was developed by [[Genta (company)|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 drugs|antisense drug]] is a short sequence of RNA that hybridises with and inactivates mRNA, preventing the [[protein]] from being formed.
Human [[lymphoma]] [[cell (biology)|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.<ref name="pmid12445555">{{cite journal | vauthors = Dias N, Stein CA | title = Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides | journal = European Journal of Pharmaceutics and Biopharmaceutics | volume = 54 | issue = 3 | pages =
These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.<ref name="pmid15010151">{{cite journal | vauthors = Mavromatis BH, Cheson BD | title = Novel therapies for chronic lymphocytic leukemia | journal = Blood Reviews | volume = 18 | issue = 2 | pages =
===ABT-737 and navitoclax (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 [[MCL1|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.<ref>{{cite journal |
In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.<ref>{{cite journal | vauthors = Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH
===Venetoclax (ABT-199)===
Due to dose-limiting thrombocytopenia of navitoclax as a result of Bcl-xL inhibition, [[Abbvie]] successfully developed the highly selective inhibitor [[venetoclax]] (ABT-199), which inhibits Bcl-2, but not Bcl-xL or Bcl-w.<ref>{{cite journal | vauthors = Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, Cortes J, DeAngelo DJ, Debose L, Mu H, Döhner H, Gaidzik VI, Galinsky I, Golfman LS, Haferlach T, Harutyunyan KG, Hu J, Leverson JD, Marcucci G, Müschen M, Newman R, Park E, Ruvolo PP, Ruvolo V, Ryan J, Schindela S, Zweidler-McKay P, Stone RM, Kantarjian H, Andreeff M, Konopleva M, Letai AG | title = Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia | journal = Cancer Discovery | volume = 4 | issue = 3 | pages =
It was approved by the [[US FDA]] in April 2016 as a second-line treatment for CLL associated with 17-p deletion.<ref name=Bankhead2016>{{cite news |last1=Bankhead |first1=Charles |title=FDA Approves AbbVie's BCL-2 Targeting Drug for CLL |url=https://www.medpagetoday.com/hematologyoncology/leukemia/57298 |work=Medpage Today |date=11 April 2016 |language=en}}</ref> This was the first FDA approval of a BCL-2 inhibitor.<ref name=Bankhead2016/> 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.<ref>{{cite web|title=FDA approves venetoclax for CLL or SLL, with or without 17p deletion, after one prior therapy|date=24 March 2020 |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm|publisher=U.S. Food and Drug Administration|language=en}}</ref>
===Sonrotoclax (BGB-11417)===
Venetoclax drug resistance has been noted with the G101V mutation in BCL-2 observed in relapsing patients.<ref>{{cite journal |
== Interactions ==
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Bcl-2 has been shown to [[Protein-protein interaction|interact]] with:
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* [[BAK1]],<ref name = pmid14980220>{{cite journal | vauthors = Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK | title = Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 | journal = Cell | volume = 116 | issue = 4 | pages =
* [[BCAP31]],<ref name = pmid9334338>{{cite journal | vauthors = Ng FW, Nguyen M, Kwan T, Branton PE, Nicholson DW, Cromlish JA, Shore GC | title = p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum | journal = The Journal of Cell Biology | volume = 139 | issue = 2 | pages =
* [[BCL2-like 1 (gene)|BCL2-like 1]],<ref name = pmid14980220/><ref name = pmid12137781>{{cite journal | vauthors = Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M | title = Development of a high-throughput fluorescence polarization assay for Bcl-x(L) | journal = Analytical Biochemistry | volume = 307 | issue = 1 | pages =
* [[BCL2L11]],<ref name = pmid15694340/><ref name = pmid9430630>{{cite journal | vauthors = O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC | title = Bim: a novel member of the Bcl-2 family that promotes apoptosis | journal = The EMBO Journal | volume = 17 | issue = 2 | pages =
* [[BECN1]],<ref name = pmid9765397>{{cite journal | vauthors = Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B | title = Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein | journal = Journal of Virology | volume = 72 | issue = 11 | pages =
* [[BH3 interacting domain death agonist|BID]],<ref name = pmid15694340/><ref name = pmid15520201>{{cite journal | vauthors = Real PJ, Cao Y, Wang R, Nikolovska-Coleska Z, Sanz-Ortiz J, Wang S, Fernandez-Luna JL | title = Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2 | journal = Cancer Research | volume = 64 | issue = 21 | pages =
* [[BMF (gene)|BMF]],<ref name = pmid11546872>{{cite journal | vauthors = Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A
* [[BNIP2]],<ref name = pmid12901880/><ref name = pmid7954800>{{cite journal | vauthors = Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G
* [[BNIP3]],<ref name = pmid7954800/><ref name = pmid10625696>{{cite journal | vauthors = Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Gietz RD, Greenberg AH | title = BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites | journal = The Journal of Biological Chemistry | volume = 275 | issue = 2 | pages =
* [[BNIPL]],<ref name = pmid12901880>{{cite journal | vauthors = Qin W, Hu J, Guo M, Xu J, Li J, Yao G, Zhou X, Jiang H, Zhang P, Shen L, Wan D, Gu J | title = BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis | journal = Biochemical and Biophysical Research Communications | volume = 308 | issue = 2 | pages =
* [[Bcl-2-associated death promoter|BAD]]<ref name = pmid15694340/><ref name = pmid7834748>{{cite journal | vauthors = Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ
* [[Bcl-2-associated X protein|BAX]],<ref name = pmid14980220/><ref name = pmid10620799/><ref name = pmid15231068>{{cite journal | vauthors = Hoetelmans RW | title = Nuclear partners of Bcl-2: Bax and PML | journal = DNA and Cell Biology | volume = 23 | issue = 6 | pages =
* [[Bcl-2-interacting killer|BIK]],<ref name = pmid15694340>{{cite journal | vauthors = Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC | title = Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function | journal = Molecular Cell | volume = 17 | issue = 3 | pages = 393–403 | date =
* [[C-Raf]],<ref name = pmid8929532>{{cite journal | vauthors = Wang HG, Rapp UR, Reed JC | title = Bcl-2 targets the protein kinase Raf-1 to mitochondria | journal = Cell | volume = 87 | issue = 4 | pages =
* [[CAPN2]],<ref name = pmid12000759>{{cite journal | vauthors = Gil-Parrado S, Fernández-Montalván A, Assfalg-Machleidt I, Popp O, Bestvater F, Holloschi A, Knoch TA, Auerswald EA, Welsh K, Reed JC, Fritz H, Fuentes-Prior P, Spiess E, Salvesen GS, Machleidt W | title = Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members | journal = The Journal of Biological Chemistry | volume = 277 | issue = 30 | pages =
* [[Caspase 8|CASP8]],<ref name = pmid11406564>{{cite journal | vauthors = Poulaki V, Mitsiades N, Romero ME, Tsokos M | title = Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2 | journal = Cancer Research | volume = 61 | issue = 12 | pages =
* [[Cdk1]],<ref name = pmid11774038>{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Basu A, Haldar S, Reed JC | title = Microtubule-targeting drugs induce bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 6 | pages =
* [[HRK (gene)|HRK]],<ref name = pmid15694340/><ref name = pmid9130713>{{cite journal | vauthors = Inohara N, Ding L, Chen S, Núñez G | title = harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L) | journal = The EMBO Journal | volume = 16 | issue = 7 | pages =
* [[IRS1]],<ref name = pmid10679027>{{cite journal | vauthors = Ueno H, Kondo E, Yamamoto-Honda R, Tobe K, Nakamoto T, Sasaki K, Mitani K, Furusaka A, Tanaka T, Tsujimoto Y, Kadowaki T, Hirai H | title = Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function | journal = Molecular Biology of the Cell | volume = 11 | issue = 2 | pages =
* [[Myc]],<ref name = pmid15210690>{{cite journal | vauthors = Jin Z, Gao F, Flagg T, Deng X | title = Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages =
* [[Nerve Growth factor IB|NR4A1]],<ref name = pmid14980220/>
* [[Noxa]],<ref name = pmid15694340/><ref name = pmid10807576>{{cite journal | vauthors = Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N | title = Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis | journal = Science | volume = 288 | issue = 5468 | pages =
* [[PPP2CA]],<ref name = pmid9852076>{{cite journal | vauthors = Deng X, Ito T, Carr B, Mumby M, May WS | title = Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A | journal = The Journal of Biological Chemistry | volume = 273 | issue = 51 | pages =
* [[PSEN1]],<ref name = pmid10521466>{{cite journal | vauthors = Alberici A, Moratto D, Benussi L, Gasparini L, Ghidoni R, Gatta LB, Finazzi D, Frisoni GB, Trabucchi M, Growdon JH, Nitsch RM, Binetti G | title = Presenilin 1 protein directly interacts with Bcl-2 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 43 | pages =
* [[RAD9A]],<ref name = pmid10620799>{{cite journal | vauthors = Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG
* [[RRAS]],<ref name = pmid8232588>{{cite journal | vauthors = Fernandez-Sarabia MJ, Bischoff JR
* [[Reticulon 4|RTN4]],<ref name = pmid11126360>{{cite journal | vauthors = Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y | title = A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity | journal = Oncogene | volume = 19 | issue = 50 | pages =
* [[SMN1]],<ref name = pmid9389483>{{cite journal | vauthors = Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y
* [[SOD1]],<ref name = pmid15233914>{{cite journal | vauthors = Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH
* [[TP53BP2]].<ref name = pmid8668206>{{cite journal | vauthors = Naumovski L, Cleary ML | title = The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M | journal = Molecular and Cellular Biology | volume = 16 | issue = 7 | pages =
{{colend}}
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