Bcl-2: Difference between revisions

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{{Infobox_gene}}
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'''Bcl-2''' ('''B-cell lymphoma 2'''), encoded in humans by the '''''BCL2''''' [[gene]], is the founding member of the [[apoptosis regulator proteins, Bcl-2 family|Bcl-2 family]] of [[regulator protein]]s that regulate cell death ([[apoptosis]]), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis.<ref name="pmid6093263">{{cite journal | vauthors = Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM | title = Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation | journal = Science | volume = 226 | issue = 4678 | pages = 1097–9 | date = Nov 1984 | pmid = 6093263 | doi = 10.1126/science.6093263 | bibcode = 1984Sci...226.1097T }}</ref><ref name="pmid2875799">{{cite journal | vauthors = Cleary ML, Smith SD, Sklar J | title = Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation | journal = Cell | volume = 47 | issue = 1 | pages = 19–28 | date = Oct 1986 | pmid = 2875799 | doi = 10.1016/0092-8674(86)90362-4 }}</ref> Bcl-2 is specifically considered an important anti-apoptotic protein but it is NOT considered a proto-oncogene because it is not a growth signal transducer.
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{{GNF_Protein_box
| Name = B-cell CLL/lymphoma 2
| HGNCid = 990
| Symbol = BCL2
| AltSymbols =; Bcl-2
| OMIM = 151430
| ECnumber = 
| Homologene = 527
| MGIid = 88138
| GeneAtlas_image1 = PBB_GE_BCL2_203685_at_tn.png
| GeneAtlas_image2 = PBB_GE_BCL2_203684_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_BCL2_207005_s_at_tn.png
| Function = {{GNF_GO|id=GO:0042802 |text = identical protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005741 |text = mitochondrial outer membrane}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0005829 |text = cytosol}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0001836 |text = release of cytochrome c from mitochondria}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0051453 |text = regulation of cellular pH}} {{GNF_GO|id=GO:0051902 |text = negative regulation of mitochondrial depolarization}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 596
    | Hs_Ensembl = ENSG00000171791
    | Hs_RefseqProtein = NP_000624
    | Hs_RefseqmRNA = NM_000633
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 18
    | Hs_GenLoc_start = 58941559
    | Hs_GenLoc_end = 59137593
    | Hs_Uniprot = P10415
    | Mm_EntrezGene = 12043
    | Mm_Ensembl = ENSMUSG00000057329
    | Mm_RefseqmRNA = NM_009741
    | Mm_RefseqProtein = NP_033871
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 1
    | Mm_GenLoc_start = 108365740
    | Mm_GenLoc_end = 108541821
    | Mm_Uniprot = Q4VBF6
  }}
}}
{{SI}}


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 14 and 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 }}</ref> (such as ''Bcl2'' in mice) have been identified in numerous [[mammals]] for which complete [[genome]] data are available.


==Overview==
Like [[BCL3]], BCL5, [[BCL6]], BCL7A, [[BCL9]], and [[BCL10]], it has clinical significance in [[lymphoma]].
'''Bcl-2''' is the prototype for a family of mammalian [[gene]]s and the [[protein]]s they produce. They govern [[mitochondria]]l outer membrane permeabilization (MOMP) and can be either pro-[[apoptosis|apoptotic]] ([[Bax_(biochemistry)|Bax]], [[Bcl-2-associated death promoter|BAD]], [[Bcl-2 homologous antagonist killer|Bak]] and Bok among others) or anti-apoptotic (including Bcl-2 proper, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date. Bcl-2 derives its name from ''B-cell lymphoma 2'', as it is the second member of a range of proteins initially described as a reciprocal gene translocation in [[chromosome]]s 14 and 18 in follicular [[lymphoma]]s.


==Function of Bcl-2==
== Isoforms ==
There are a number of theories concerning how the Bcl-2 gene family exert their pro- or anti-apoptotic effect. An important one states that this is achieved by activation or inactivation of an inner [[mitochondrial permeability transition pore]], which is involved in the regulation of matrix [[calcium in biology|Ca<sup>2+</sup>]], [[pH]], and voltage. It is also thought that some Bcl-2 family proteins can induce (pro-apoptotic members) or inhibit (anti-apoptotic members) the release of [[cytochrome c]] in to the [[cytosol]] which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Although Zamzami et al. suggest that the release of cytochrome c is indirectly mediated by the PT pore on the inner mitochondrial membrane, <ref>Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G. ''Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins.'' Oncogene 1998;16:2265-82. PMID 9619836</ref> strong evidences suggest an earlier implication of the [[MAC, the Mitochondrial Apoptosis-Induced Channel|MAC]] pore on the outer membrane.<ref>Kinnally, K.W., Antonsson, B. ''A tale of two mitochondrial channels, MAC and PTP, in apoptosis.'' Apoptosis 2007;12(5):857-868. PMID 17294079</ref><ref>Martinez-Caballero S, Dejean LM, Jonas EA, Kinnally KW. ''The role of the mitochondrial apoptosis induced channel MAC in cytochrome c release.'' J. Bioenerg. Biomembr. 2005;37:155-164. PMID 16167172</ref>


[[Image:Bcl-2 Family.jpg|left|thumb|300px|Bcl-2 family<ref>Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395-419. Review.</ref>]]
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 [[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">{{cite web | title = Human Bcl2, Isoform 1 | url = http://www.rcsb.org/pdb/explore/explore.do?structureId=1G5M }}</ref>


The members of the Bcl-2 family share one or more of the four characteristic [[Domain (biology)|domain]]s of [[Homology (biology)|homology]] entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4) (see the figure on your left). The BH domains are known to be crucial for function, as deletion of these domains via molecular [[cloning]] affects survival/apoptosis rates. The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and [[Bcl-xL]], conserve all four BH domains. The BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins into those with several BH domains (e.g. [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|Bak]]) or those proteins that have only the BH3 domain (e.g. Bid, [[BCL2L11|Bim]] and Bad). The Bcl-2 family has a general structure that consists of a [[Hydrophobe|hydrophobic]] helix surrounded by amphipathic helices. Many members of the family have [[Transmembrane_proteins|transmembrane domain]]s. The site of action for the Bcl-2 family is mostly on the outer mitochondrial membrane. Within the mitochondria are apoptogenic factors (cytochrome c, Smac/DIABLO, Omi) that if released activate the executioners of apoptosis, the [[caspase]]s.<ref name="caspcontrol">{{cite journal | author=Fesik SW, Shi Y.| title=Controlling the caspases| journal=Science| year=2001| volume=294| issue=5546| page=1477–1478| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11711663}}</ref> Depending on their function, once activated, Bcl-2 proteins either promote the release of these factors, or keep them sequestered in the mitochondria. Whereas the activated pro-apoptotic Bak and/or Bax would form [[MAC, the Mitochondrial Apoptosis-Induced Channel|MAC]] and mediate the release of cytochrome c, the anti-apoptotic Bcl-2 would block it, possibly through inhibition of Bax and/or Bak.<ref>Dejean LM, Martinez-Caballero S, Manon S, Kinnally KW. ''Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins.'' Biochim. Biophys. Acta. 2006;1762(2):191-201. PMID 16055309 </ref>
==Normal physiological function==


==Role in disease==
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 [[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|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 |pmid=23378584 | doi=10.1101/cshperspect.a008722 | volume=5 | issue=2 | title=Multiple functions of BCL-2 family proteins | pmc=3552500 | year=2013 | journal=Cold Spring Harb Perspect Biol | vauthors=Hardwick JM, Soane L | pages=a008722}}</ref>
The Bcl-2 gene has been implicated in a number of [[cancer]]s, including [[melanoma]], [[breast cancer|breast]], [[prostate cancer|prostate]], and [[lung cancer|lung carcinomas]], as well as [[schizophrenia]] and [[autoimmunity]]. It is also thought to be involved in resistance to conventional cancer treatment. This supports a role for decreased apoptosis in the pathogenesis of cancer.
[[Schizophrenia]] is a [[neurodegenerative]] chronic illness that affects about 60 million individuals world wide and is characterized by hallucinations, disorderly thought, delusions and changes in sensitivity and emotional state.  The mechanism of apoptosis is connected to schizophrenia because it is known to occur in the early development of the nervous system and also eliminates injured or diseased neurons throughout life. (Schizophrenia Research. 2006; 81, 47–63). An increase in apoptosis caused by stresses such as excessive calcium flux, oxidative stress and mitochondrial dysfunction, has been found in schizophrenia. This apoptotic activity is localized in the synapses and neuritis, whose structural components contain substrates for caspases.  Researchers have found that increasing apoptotic stimuli, increased caspase-3 activity, thus degenerating the neuritis and synaptic spines.  "The stresses, mentioned above, increase the ratio of pro/anti-apoptotic factors, therefore increasing the likelihood of this caspase activity event which leads to schizophrenia." (Schizophrenia Research. 2006; 81, 47–63).


Apoptosis also plays a very 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." (Clinical and Developmental Immunology. 2006. 13(2-4); 273-282). 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 (DCs) are of the most important antigen presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. "Researchers have found that mice containing DCs that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal DCs."(Clinical and Developmental Immunology. 2006. 13(2-4); 273-282). "Other studies have shown that the lifespan of DCs may be controlled by factors such as a timer dependent on anti-apoptotic Bcl-2." (Clinical and Developmental Immunology. 2006. 13(2-4); 273-282). These investigations illuminate the importance of regulating antigen presentation as mis-regulation can lead to autoimmunity.
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|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 |pmc= 3552500 |year=2016 |journal= Endocrinology |vauthors= Aharoni-Simon M, Shumiatcher R, Yeung A, Shih AZ, Dolinsky VW, Doucette CA, Luciani DS |pages= 2270-2281}}</ref>


Cancer is one of the worlds leading causes of death and occurs when the homeostatic balance between cell growth and death is disturbed.  Research in cancer biology has discovered that a variety of aberrations in gene expression of anti-apoptotic, pro-apoptotic and BH3-only proteins can contribute to the many forms of the disease.  An interesting example can be seen in lymphomas.  The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone did not act in an oncogenic manner.  "Its combined expression with the cell cycle mitogen promoting myc gene led to an aggressive malignancy of the B-cell lineage leading to the creation of lymphomas." (Blood. 2007. 1; 16).
== Role in disease ==
In [[non-Hodgkin lymphoma|follicular B-cell lymphoma]], a [[chromosomal translocation]] occurs between the fourteenth and the eighteenth [[chromosome]]s - t(14;18) - which places the Bcl-2 gene next to the [[immunoglobulin]] heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of anti-apoptotic ''bcl-2'' protein.<ref>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;335:440-2. PMID: 3262202.</ref> This decreases the propensity of these cells for undergoing apoptosis.
{{See also|Apoptosis#Implication_in_disease|label 1 = Apoptosis implication in disease}}


Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. Bcl-2 is essential to the process of apoptosis because it suppresses the initiation of the cell-death process.
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.{{citation needed|date=June 2016}}
Further research into the family of Bcl-2 proteins will provide us with a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis. An understanding of the mechanisms involved will help us find potential treatments such as inhibitors to target over-expressed proteins that may lead to disabling diseases such as cancer, neurodegenerative diseases and autoimmunity.


==Targeted therapies==
===Cancer===
An antisense [[oligonucleotide]] drug Genasense (G3139) has been developed 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 which hybridises with and inactivates mRNA, preventing the protein from being formed.
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 = 3069–75 | date = Apr 2007 | pmid = 17179226 | pmc = 1852223 | doi = 10.1182/blood-2006-08-043257 }}</ref> In [[follicular lymphoma]], a [[chromosomal translocation]] commonly occurs between the fourteenth and the eighteenth [[chromosome]]s — t(14;18) — which places the Bcl-2 gene from chromosome 18 next to the [[Immunoglobulin superfamily|immunoglobulin]] heavy chain locus on chromosome 14. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.<ref name="pmid3262202">{{cite journal | vauthors = Vaux DL, Cory S, Adams JM | title = Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells | journal = Nature | volume = 335 | issue = 6189 | pages = 440–2 | date = Sep 1988 | pmid = 3262202 | doi = 10.1038/335440a0 | bibcode = 1988Natur.335..440V }}</ref> This decreases the propensity of these cells for apoptosis.


It was shown that the proliferation of human [[lymphoma]] [[cell (biology)|cells]] (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>Dias N, Stein CA. ''Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides.'' Eur J Pharm Biopharm 2002;54:263-9. PMID 12445555.</ref>
===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 = 273–82 | year = 2006 | pmid = 17162368 | pmc = 2270759 | doi = 10.1080/17402520600834704 }}</ref> The autoimmune disease [[Diabetes mellitus type 1|type 1 diabetes]] can be caused by defective apoptosis, which leads to aberrant T cell [[Activation-induced cytidine deaminase|AICD]] and defective peripheral tolerance. Due to the fact that [[dendritic cell]]s are the immune system's most important [[antigen-presenting cell]]s, their activity must be tightly regulated by mechanisms such as apoptosis. Researchers have found that mice containing dendritic cells that are [[BCL2L11|Bim]] -/-, thus unable to induce effective apoptosis, suffer [[autoimmune disease]]s more so than those that have normal dendritic cells.<ref name="pmid17162368"/> Other studies have shown that  dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.<ref name="pmid17162368"/>


These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway (Mavoromatis and Cheson 2004).
=== Other ===


Genasense did not receive [[Food and Drug Administration|FDA]] approval after disappointing results in a melanoma trial.
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.<ref name="pmid16226876">{{cite journal | vauthors = Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF | title = Apoptotic mechanisms and the synaptic pathology of schizophrenia | journal = Schizophrenia Research | volume = 81 | issue = 1 | pages = 47–63 | date = Jan 2006 | pmid = 16226876 | doi = 10.1016/j.schres.2005.08.014 }}</ref> Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of [[Caspase 3|caspase-3]].<ref name="pmid16226876"/>


Abbott has recently described a novel inhibitor of Bcl-2 and Bcl-xL, known as ABT-737.<ref>Oltersdorf T, et al. ''An inhibitor of Bcl-2 family proteins induces regression of solid tumours.'' Nature. 435:677-681. PMID: 15902208</ref>.  ABT-737 is one among many so-called BH3 mimetic small molecule inhibitors (SMI) targeting Bcl-2 and Bcl-2-related proteins such as Bcl-xL and [[Mcl-1]], which may prove valuable in the therapy of lymphoma and other blood cancers.<ref>John C. Reed, and Maurizio Pellecchia, "Apoptosis-based therapies for hematologic malignancies", Blood. 106(2):408-418 (2005). PMID: 15797997</ref>.
== Diagnostic use ==


==See also==
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|author=Leong, Anthony S-Y|author2=Cooper, Kumarason|author3=Leong, F Joel W-M|year=2003|title=Manual of Diagnostic Cytology|edition=2|publisher=Greenwich Medical Media, Ltd.|pages=XX|isbn=1-84110-100-1}}</ref>
 
== Targeted therapies ==
 
Targeted and selective Bcl-2 inhibitors currently in the clinic include:
 
===Oblimersen===
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 = 263–9 | date = Nov 2002 | pmid = 12445555 | doi = 10.1016/S0939-6411(02)00060-7 | url = http://linkinghub.elsevier.com/retrieve/pii/S0939641102000607 }}</ref>
 
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 = 137–48 | date = Jun 2004 | pmid = 15010151 | doi = 10.1016/S0268-960X(03)00039-0 }}</ref> As of 2016, the drug had not been approved and its developer was out of business.<ref>{{Cite web|title = Genasense (oblimersen sodium) FDA Approval Status - Drugs.com|url = http://www.drugs.com/history/genasense.html|website = www.drugs.com|access-date = 2016-02-11}}</ref>
 
===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 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>Vogler, Meike, et al. "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy." Cell Death & Differentiation 16.3 (2008): 360–367.</ref> 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.{{Citation needed|reason=Claim that ABT-737 does not directly induce apoptosis is not supported|date=January 2017}}
 
In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.<ref>{{cite journal | author = Oltersdorf T ''et al'' | year = 2005 | title = An inhibitor of Bcl-2 family proteins induces regression of solid tumours | url = | journal = Nature | volume = 435 | issue = 7042| pages = 677–681 | doi=10.1038/nature03579 | pmid=15902208| bibcode = 2005Natur.435..677O }}</ref> In preclinical studies utilizing [[Patient derived tumor xenografts|patient xenografts]], ABT-737 showed efficacy for treating lymphoma and other blood cancers.<ref>{{cite journal | author = Hann CL | year = 2008 | title = Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer | url = | journal = Cancer Research | volume = 68 | issue = 7| pages = 2321–2328 | doi=10.1158/0008-5472.can-07-5031| pmid = 18381439 | pmc = 3159963 |display-authors=etal}}</ref> Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its orally [[Bioavailability|bioavailable]] derivative [[navitoclax]] (ABT-263) has similar activity on [[small cell lung cancer]] (SCLC) cell lines and has entered clinical trials.<ref name="hauck2009">{{cite web|url=http://mct.aacrjournals.org/content/8/4/883.full.html|title=Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737|publisher=}}</ref> While clinical responses with navitoclax were promising, mechanistic dose-limiting [[Thrombocytopenia|thrombocytopoenia]] was observed in patients under treatment due to Bcl-xL inhibition in [[platelet]]s.<ref>{{Cite journal|last=Gandhi|first=Leena|last2=Camidge|first2=D. Ross|last3=Ribeiro de Oliveira|first3=Moacyr|last4=Bonomi|first4=Philip|last5=Gandara|first5=David|last6=Khaira|first6=Divis|last7=Hann|first7=Christine L.|last8=McKeegan|first8=Evelyn M.|last9=Litvinovich|first9=Elizabeth|date=2011-03-01|title=Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=29|issue=7|pages=909–916|doi=10.1200/JCO.2010.31.6208|issn=1527-7755|pmc=4668282|pmid=21282543}}</ref><ref>{{Cite journal|last=Rudin|first=Charles M.|last2=Hann|first2=Christine L.|last3=Garon|first3=Edward B.|last4=Ribeiro de Oliveira|first4=Moacyr|last5=Bonomi|first5=Philip D.|last6=Camidge|first6=D. Ross|last7=Chu|first7=Quincy|last8=Giaccone|first8=Giuseppe|last9=Khaira|first9=Divis|date=2012-06-01|title=Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer|journal=Clinical Cancer Research|volume=18|issue=11|pages=3163–3169|doi=10.1158/1078-0432.CCR-11-3090|issn=1078-0432|pmc=3715059|pmid=22496272}}</ref><ref>{{Cite journal|last=Kaefer|first=Aksana|last2=Yang|first2=Jianning|last3=Noertersheuser|first3=Peter|last4=Mensing|first4=Sven|last5=Humerickhouse|first5=Rod|last6=Awni|first6=Walid|last7=Xiong|first7=Hao|date=2014-09-01|title=Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia|journal=Cancer Chemotherapy and Pharmacology|volume=74|issue=3|pages=593–602|doi=10.1007/s00280-014-2530-9|issn=1432-0843|pmid=25053389}}</ref>
 
===Venetoclax (ABT-199)===
Due to dose-limiting thrombocytopoenia 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|last=Pan|first=Rongqing|last2=Hogdal|first2=Leah J.|last3=Benito|first3=Juliana M.|last4=Bucci|first4=Donna|last5=Han|first5=Lina|last6=Borthakur|first6=Gautam|last7=Cortes|first7=Jorge|last8=DeAngelo|first8=Daniel J.|last9=Debose|first9=Lakeisha|date=2014-03-01|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=362–375|doi=10.1158/2159-8290.CD-13-0609|issn=2159-8290|pmc=3975047|pmid=24346116}}</ref> Clinical trials studied the effects of venetoclax, a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with [[chronic lymphocytic leukemia]] (CLL).<ref>{{cite news |title=ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia |first=Grace |last=Liao |date=August 12, 2011 |url=http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia |publisher=Asian Scientist |accessdate=February 2016 |deadurl=yes |archiveurl=https://web.archive.org/web/20120718151431/http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia/ |archivedate=18 July 2012 |df=dmy }}</ref><ref name=":0">{{Cite journal|last=Roberts|first=Andrew W.|last2=Davids|first2=Matthew S.|last3=Pagel|first3=John M.|last4=Kahl|first4=Brad S.|last5=Puvvada|first5=Soham D.|last6=Gerecitano|first6=John F.|last7=Kipps|first7=Thomas J.|last8=Anderson|first8=Mary Ann|last9=Brown|first9=Jennifer R.|date=2016-01-28|title=Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia|journal=The New England Journal of Medicine|volume=374|issue=4|pages=311–322|doi=10.1056/NEJMoa1513257|issn=1533-4406|pmid=26639348}}</ref> Good responses have been reported and thrombocytopoenia was no longer observed.<ref name=":0" /><ref>{{cite web|url=http://www.stokesentinel.co.uk/Miracle-drug-cured-cancer-Amazing-recovery/story-21080535-detail/story.html|title='Miracle drug cured my cancer!': Amazing three-week recovery of Staffordshire sufferer|work=Stoke Sentinel}}</ref> A phase 3 trial started in Dec 2015.<ref name=ASH2015-V>{{cite web|url=http://www.medpagetoday.com/MeetingCoverage/ASHHematology/55056|title=Hard-to-Treat CLL Yields to Investigational Drug|author=Michael Smith |date=7 December 2015 |publisher=}}</ref>
It was approved by the [[US FDA]] in April 2016 for CLL associated with 17-p deletion.<ref name=Bankhead2016>[chronic lymphocytic leukemia (CLL) associated with 17-p deletion. FDA Approves AbbVie's BCL-2 Targeting Drug for CLL. April 2016]</ref> This is the first FDA approval of a protein-protein inhibitor of BCL-2.<ref name=Bankhead2016/>
 
== Interactions ==
 
[[Image:Signal transduction pathways.svg|thumb|right|Overview of signal transduction pathways involved in [[apoptosis]].]]
Bcl-2 has been shown to [[Protein-protein interaction|interact]] with:
{{colbegin|3}}
* [[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 = 527–40 | date = Feb 2004 | pmid = 14980220 | doi = 10.1016/s0092-8674(04)00162-x }}</ref><ref name = pmid11728179>{{cite journal | vauthors = Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X, Huang Y, Long YQ, Roller PP, Yang D, Wang S | title = Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 25 | pages = 4313–24 | date = Dec 2001 | pmid = 11728179 | doi = 10.1021/jm010016f }}</ref>
* [[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 = 327–38 | date = Oct 1997 | pmid = 9334338 | pmc = 2139787 | doi = 10.1083/jcb.139.2.327 }}</ref>
* [[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 = 70–5 | date = Aug 2002 | pmid = 12137781 | doi = 10.1016/s0003-2697(02)00028-3 }}</ref>
* [[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 = 384–95 | date = Jan 1998 | pmid = 9430630 | pmc = 1170389 | doi = 10.1093/emboj/17.2.384 }}</ref><ref name = pmid9731710>{{cite journal | vauthors = Hsu SY, Lin P, Hsueh AJ | title = BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members | journal = Molecular Endocrinology | volume = 12 | issue = 9 | pages = 1432–40 | date = Sep 1998 | pmid = 9731710 | doi = 10.1210/mend.12.9.0166 }}</ref>
* [[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 = 8586–96 | date = Nov 1998 | pmid = 9765397 | pmc = 110269 | doi =  }}</ref>
* [[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 = 7947–53 | date = Nov 2004 | pmid = 15520201 | doi = 10.1158/0008-5472.CAN-04-0945 }}</ref>
* [[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 | title = Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis | journal = Science | volume = 293 | issue = 5536 | pages = 1829–32 | date = Sep 2001 | pmid = 11546872 | doi = 10.1126/science.1062257 | bibcode = 2001Sci...293.1829P }}</ref>
* [[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 | title = Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins | journal = Cell | volume = 79 | issue = 2 | pages = 341–51 | date = Oct 1994 | pmid = 7954800 | doi = 10.1016/0092-8674(94)90202-X }}</ref>
* [[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 = 1439–48 | date = Jan 2000 | pmid = 10625696 | doi = 10.1074/jbc.275.2.1439 }}</ref>
* [[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 = 379–85 | date = Aug 2003 | pmid = 12901880 | doi = 10.1016/s0006-291x(03)01387-1 }}</ref><ref name = pmid9973195>{{cite journal | vauthors = Yasuda M, Han JW, Dionne CA, Boyd JM, Chinnadurai G | title = BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3 | journal = Cancer Research | volume = 59 | issue = 3 | pages = 533–7 | date = Feb 1999 | pmid = 9973195 | doi =  }}</ref>
* [[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 | title = Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death | journal = Cell | volume = 80 | issue = 2 | pages = 285–91 | date = Jan 1995 | pmid = 7834748 | doi = 10.1016/0092-8674(95)90411-5 }}</ref>
* [[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 = 351–4 | date = Jun 2004 | pmid = 15231068 | doi = 10.1089/104454904323145236 }}</ref><ref name = pmid8358790>{{cite journal | vauthors = Oltvai ZN, Milliman CL, Korsmeyer SJ | title = Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death | journal = Cell | volume = 74 | issue = 4 | pages = 609–19 | date = Aug 1993 | pmid = 8358790 | doi = 10.1016/0092-8674(93)90509-O }}</ref>
* [[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 = Feb 2005 | pmid = 15694340 | doi = 10.1016/j.molcel.2004.12.030 }}</ref><ref name = pmid12853473>{{cite journal | vauthors = Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT | title = Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway | journal = The EMBO Journal | volume = 22 | issue = 14 | pages = 3580–90 | date = Jul 2003 | pmid = 12853473 | pmc = 165613 | doi = 10.1093/emboj/cdg343 }}</ref>
* [[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 = 629–38 | date = Nov 1996 | pmid = 8929532 | doi = 10.1016/s0092-8674(00)81383-5 }}</ref>
* [[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 = 27217–26 | date = Jul 2002 | pmid = 12000759 | doi = 10.1074/jbc.M202945200 }}</ref>
* [[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 = 4864–72 | date = Jun 2001 | pmid = 11406564 | doi =  }}</ref><ref name = pmid11832478>{{cite journal | vauthors = Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES | title = Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 13430–7 | date = Apr 2002 | pmid = 11832478 | doi = 10.1074/jbc.M108029200 }}</ref>
* [[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 = 550–9 | pmid = 11774038 | pmc = 1506558 | doi = 10.1038/sj.neo.7900213 | year = 2001 }}</ref><ref name = pmid11326318>{{cite journal | vauthors = Pathan N, Aime-Sempe C, Kitada S, Haldar S, Reed JC | title = Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1 | journal = Neoplasia | volume = 3 | issue = 1 | pages = 70–9 | pmid = 11326318 | pmc = 1505024 | doi = 10.1038/sj.neo.7900131 | year = 2001 }}</ref>
* [[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 = 1686–94 | date = Apr 1997 | pmid = 9130713 | pmc = 1169772 | doi = 10.1093/emboj/16.7.1686 }}</ref>
* [[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 = 735–46 | date = Feb 2000 | pmid = 10679027 | pmc = 14806 | doi = 10.1091/mbc.11.2.735 }}</ref>
* [[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 = 40209–19 | date = Sep 2004 | pmid = 15210690 | doi = 10.1074/jbc.M404056200 }}</ref>
* [[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 = 1053–8 | date = May 2000 | pmid = 10807576 | doi = 10.1126/science.288.5468.1053 | bibcode = 2000Sci...288.1053O }}</ref>
* [[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 = 34157–63 | date = Dec 1998 | pmid = 9852076 | doi = 10.1074/jbc.273.51.34157 }}</ref>
* [[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 = 30764–9 | date = Oct 1999 | pmid = 10521466 | doi = 10.1074/jbc.274.43.30764 }}</ref>
* [[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 | title = Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis | journal = Nature Cell Biology | volume = 2 | issue = 1 | pages = 1–6 | date = Jan 2000 | pmid = 10620799 | doi = 10.1038/71316 }}</ref>
* [[RRAS]],<ref name = pmid8232588>{{cite journal | vauthors = Fernandez-Sarabia MJ, Bischoff JR | title = Bcl-2 associates with the ras-related protein R-ras p23 | journal = Nature | volume = 366 | issue = 6452 | pages = 274–5 | date = Nov 1993 | pmid = 8232588 | doi = 10.1038/366274a0 | bibcode = 1993Natur.366..274F }}</ref>
* [[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 = 5736–46 | date = Nov 2000 | pmid = 11126360 | doi = 10.1038/sj.onc.1203948 }}</ref>
* [[SMN1]],<ref name = pmid9389483>{{cite journal | vauthors = Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y | title = Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy | journal = Nature | volume = 390 | issue = 6658 | pages = 413–7 | date = Nov 1997 | pmid = 9389483 | doi = 10.1038/37144 | bibcode = 1997Natur.390..413I }}</ref>
* [[SOD1]],<ref name = pmid15233914>{{cite journal | vauthors = Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH | title = Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria | journal = Neuron | volume = 43 | issue = 1 | pages = 19–30 | date = Jul 2004 | pmid = 15233914 | doi = 10.1016/j.neuron.2004.06.021 }}</ref>  and
* [[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 = 3884–92 | date = Jul 1996 | pmid = 8668206 | pmc = 231385 | doi =  }}</ref>
{{colend}}
 
==Human BCL-2 genes==
[[Bcl-2 homologous antagonist killer|BAK]]; [[BAK1]]; [[Bcl-2-associated X protein|BAX]]; [[BCL2]]; [[BCL2A1]]; [[BCL2L1]]; [[BCL2L10]]; [[BCL2L13]];
[[BCL2L14]]; [[BCL2L2]]; [[BCL2L7P1]]; [[BOK (gene)|BOK]]; [[MCL1]]; LGALS7 (Galectin-7)
 
== See also ==
{{colbegin|2}}
* [[Apoptosis]]
* [[Apoptosis]]
* [[Apoptosome]]
* [[Apoptosome]]
* [[Bcl-2-associated_X_protein]] (BAX)
* [[Bcl-2 homologous antagonist killer]] (BAK)
* [[Bcl-2-associated X protein]] (BAX)
* [[Bcl-xL]]
* [[BH3 interacting domain death agonist]] (BID)
* [[BH3 interacting domain death agonist]] (BID)
* [[Caspases]]
* [[Caspases]]
* [[Cytochrome c]]
* [[Cytochrome c]]
* [[Noxa]]
* [[Noxa]]
* [[Mcl-1]]
* [[Mitochondrion]]
* [[Mitochondrion]]
* [[Microphthalmia-associated transcription factor]]
* [[Protein mimetic]]
* [[p53 upregulated modulator of apoptosis]] (PUMA)
* [[p53 upregulated modulator of apoptosis]] (PUMA)
{{colend}}
* [[Senolytics]]


==References==
== References ==
{{Reflist|2}}
{{Reflist|33em}}


==External links==
== External links ==
* [https://web.archive.org/web/20090221095442/http://bcl2db.ibcp.fr/site/ The Bcl-2 Family Database]
* [http://www.celldeath.de/encyclo/misc/bcl2.htm The Bcl-2 Family at celldeath.de]
* [http://www.celldeath.de/encyclo/misc/bcl2.htm The Bcl-2 Family at celldeath.de]
* [http://www.caspases.org/showpopterms.php?search=Bcl-2 Bcl-2 publications sorted by impact at caspases.org]
* [http://www.caspases.org/showpopterms.php?search=Bcl-2 Bcl-2 publications sorted by impact at caspases.org]
* {{MeshName|bcl-2+Genes}}
* {{MeshName|bcl-2+Genes}}
* {{MeshName|c-bcl-2+Proteins}}
* {{MeshName|c-bcl-2+Proteins}}
* {{UCSC gene info|BCL2}}


{{Oncogenes}}
{{Oncogenes}}
{{Fas apoptosis signaling pathway}}


[[Category:Genes]]
[[Category:Human genes]]
[[Category:Integral membrane proteins]]
[[Category:Integral membrane proteins]]
[[Category:Peripheral membrane proteins]]
[[Category:Peripheral membrane proteins]]
[[Category:Oncogenes]]
[[Category:Apoptosis]]
[[Category:Apoptosis]]
[[Category:Programmed cell death]]
[[Category:Programmed cell death]]
[[es:Bcl-2]]
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Revision as of 08:22, 6 December 2017

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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 but it is NOT considered a proto-oncogene because it is not a growth signal transducer.

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 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.[5]

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,[6] but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.[7]

Role in disease

See also: Apoptosis implication 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.[citation needed]

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.[8] 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.[9] 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.[10] 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.[10] Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.[10]

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.[11] Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[11]

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.[12]

Targeted therapies

Targeted and selective Bcl-2 inhibitors currently in the clinic include:

Oblimersen

An antisense oligonucleotide drug, oblimersen (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.[13]

These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.[14] As of 2016, the drug had not been approved and its developer was out of business.[15]

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 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.[16] 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.[citation needed]

In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.[17] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.[18] Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its orally bioavailable derivative navitoclax (ABT-263) has similar activity on small cell lung cancer (SCLC) cell lines and has entered clinical trials.[19] While clinical responses with navitoclax were promising, mechanistic dose-limiting thrombocytopoenia was observed in patients under treatment due to Bcl-xL inhibition in platelets.[20][21][22]

Venetoclax (ABT-199)

Due to dose-limiting thrombocytopoenia 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.[23] Clinical trials studied the effects of venetoclax, a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia (CLL).[24][25] Good responses have been reported and thrombocytopoenia was no longer observed.[25][26] A phase 3 trial started in Dec 2015.[27] It was approved by the US FDA in April 2016 for CLL associated with 17-p deletion.[28] This is the first FDA approval of a protein-protein inhibitor of BCL-2.[28]

Interactions

File:Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

Bcl-2 has been shown to interact with:

Human BCL-2 genes

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

See also

References

  1. ↑ Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (Nov 1984). "Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation". Science. 226 (4678): 1097–9. Bibcode:1984Sci...226.1097T. doi:10.1126/science.6093263. PMID 6093263.
  2. ↑ Cleary ML, Smith SD, Sklar J (Oct 1986). "Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation". Cell. 47 (1): 19–28. doi:10.1016/0092-8674(86)90362-4. PMID 2875799.
  3. ↑ "OrthoMaM phylogenetic marker: Bcl-2 coding sequence".
  4. ↑ "Human Bcl2, Isoform 1".
  5. ↑ Hardwick JM, Soane L (2013). "Multiple functions of BCL-2 family proteins". Cold Spring Harb Perspect Biol. 5 (2): a008722. doi:10.1101/cshperspect.a008722. PMC 3552500. PMID 23378584.
  6. ↑ Luciani DS, White SA, Widenmaier SB, Saran VV, Taghizadeh F, Hu X, Allard MF, Johnson JD (2013). "Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ß-cells". Diabetes. 62 (1): 170–182. doi:10.2337/db11-1464. PMC 3526034. PMID 22933114.
  7. ↑ Aharoni-Simon M, Shumiatcher R, Yeung A, Shih AZ, Dolinsky VW, Doucette CA, Luciani DS (2016). "Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ß-Cells". Endocrinology. 157 (6): 2270–2281. doi:10.1210/en.2015-1964. PMC 3552500. PMID 27070098.
  8. ↑ Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ (Apr 2007). "Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA". Blood. 109 (7): 3069–75. doi:10.1182/blood-2006-08-043257. PMC 1852223. PMID 17179226.
  9. ↑ Vaux DL, Cory S, Adams JM (Sep 1988). "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells". Nature. 335 (6189): 440–2. Bibcode:1988Natur.335..440V. doi:10.1038/335440a0. PMID 3262202.
  10. ↑ 10.0 10.1 10.2 Li A, Ojogho O, Escher A (2006). "Saving death: apoptosis for intervention in transplantation and autoimmunity". Clinical & Developmental Immunology. 13 (2–4): 273–82. doi:10.1080/17402520600834704. PMC 2270759. PMID 17162368.
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  12. ↑ Leong, Anthony S-Y; Cooper, Kumarason; Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. XX. ISBN 1-84110-100-1.
  13. ↑ Dias N, Stein CA (Nov 2002). "Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides". European Journal of Pharmaceutics and Biopharmaceutics. 54 (3): 263–9. doi:10.1016/S0939-6411(02)00060-7. PMID 12445555.
  14. ↑ Mavromatis BH, Cheson BD (Jun 2004). "Novel therapies for chronic lymphocytic leukemia". Blood Reviews. 18 (2): 137–48. doi:10.1016/S0268-960X(03)00039-0. PMID 15010151.
  15. ↑ "Genasense (oblimersen sodium) FDA Approval Status - Drugs.com". www.drugs.com. Retrieved 2016-02-11.
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  19. ↑ "Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737".
  20. ↑ Gandhi, Leena; Camidge, D. Ross; Ribeiro de Oliveira, Moacyr; Bonomi, Philip; Gandara, David; Khaira, Divis; Hann, Christine L.; McKeegan, Evelyn M.; Litvinovich, Elizabeth (2011-03-01). "Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 29 (7): 909–916. doi:10.1200/JCO.2010.31.6208. ISSN 1527-7755. PMC 4668282. PMID 21282543.
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