Biology:Bcl-2

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Short description: Protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis.[1][2] It was the first apoptosis regulator identified in any organism.[3]

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[4] (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, and Isoform 2, 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.[5]

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.[6]

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,[7] but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.[8]

Role in disease

Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.[9]

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.[10] 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.[11] This decreases the propensity of these cells for apoptosis. Bcl-2 expression is frequent in small cell lung cancer, accounting for 76% cases in one study.[12]

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.[13] 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, have autoimmune diseases more so than those that have normal dendritic cells.[13] Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.[13]

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.[14] Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[14]

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.[15]

Targeted therapies

Targeted and selective Bcl-2 inhibitors that have been in development or are 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.[16]

These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.[17] As of 2016, the drug had not been approved and its developer was out of business.[18]

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.[19] 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.[20] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.[21] 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.[22] While clinical responses with navitoclax were promising, mechanistic dose-limiting thrombocytopenia was observed in patients under treatment due to Bcl-xL inhibition in platelets.[23][24][25]

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.[26] 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).[27][28] Good responses have been reported and thrombocytopenia was no longer observed.[28][29] A phase 3 trial started in Dec 2015.[30] It was approved by the US FDA in April 2016 as a second-line treatment for CLL associated with 17-p deletion.[31] This was the first FDA approval of a BCL-2 inhibitor.[31] 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.[32]

Interactions

Overview of signal transduction pathways involved in apoptosis

Bcl-2 has been shown to interact with:


See also

  • Senolytics

References

  1. ↑ "Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation". Science 226 (4678): 1097–9. Nov 1984. doi:10.1126/science.6093263. PMID 6093263. Bibcode: 1984Sci...226.1097T. 
  2. ↑ "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. Oct 1986. doi:10.1016/0092-8674(86)90362-4. PMID 2875799. 
  3. ↑ "Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy". Annual Review of Cancer Biology 4: 299–313. 2020. doi:10.1146/annurev-cancerbio-030419-033510. 
  4. ↑ "OrthoMaM phylogenetic marker: Bcl-2 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000171791_BCL2.xml. 
  5. ↑ PDB: 1G5M​; "Solution structure of the antiapoptotic protein bcl-2". Proceedings of the National Academy of Sciences of the United States of America 98 (6): 3012–7. March 2001. doi:10.1073/pnas.041619798. PMID 11248023. Bibcode: 2001PNAS...98.3012P. 
  6. ↑ "Multiple functions of BCL-2 family proteins". Cold Spring Harb Perspect Biol 5 (2): a008722. 2013. doi:10.1101/cshperspect.a008722. PMID 23378584. 
  7. ↑ "Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ß-cells". Diabetes 62 (1): 170–182. 2013. doi:10.2337/db11-1464. PMID 22933114. 
  8. ↑ "Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ß-Cells". Endocrinology 157 (6): 2270–2281. 2016. doi:10.1210/en.2015-1964. PMID 27070098. 
  9. ↑ "Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy". International Journal of Molecular Sciences 19 (12): 3950. Dec 2018. doi:10.3390/ijms19123950. PMID 30544835. 
  10. ↑ "Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA". Blood 109 (7): 3069–75. Apr 2007. doi:10.1182/blood-2006-08-043257. PMID 17179226. 
  11. ↑ "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells". Nature 335 (6189): 440–2. Sep 1988. doi:10.1038/335440a0. PMID 3262202. Bibcode: 1988Natur.335..440V. 
  12. ↑ Kaiser, U.; Schilli, M.; Haag, U.; Neumann, K.; Kreipe, H.; Kogan, E.; Havemann, K. (August 1996). "Expression of bcl-2 — protein in small cell lung cancer". Lung Cancer 15 (1): 31–40. doi:10.1016/0169-5002(96)00568-5. PMID 8865121. 
  13. ↑ 13.0 13.1 13.2 "Saving death: apoptosis for intervention in transplantation and autoimmunity". Clinical & Developmental Immunology 13 (2–4): 273–82. 2006. doi:10.1080/17402520600834704. PMID 17162368. 
  14. ↑ 14.0 14.1 "Apoptotic mechanisms and the synaptic pathology of schizophrenia". Schizophrenia Research 81 (1): 47–63. Jan 2006. doi:10.1016/j.schres.2005.08.014. PMID 16226876. 
  15. ↑ 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 978-1-84110-100-2. 
  16. ↑ "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. Nov 2002. doi:10.1016/S0939-6411(02)00060-7. PMID 12445555. 
  17. ↑ "Novel therapies for chronic lymphocytic leukemia". Blood Reviews 18 (2): 137–48. Jun 2004. doi:10.1016/S0268-960X(03)00039-0. PMID 15010151. 
  18. ↑ "Genasense (oblimersen sodium) FDA Approval Status - Drugs.com". https://www.drugs.com/history/genasense.html. 
  19. ↑ Vogler, M.; Dinsdale, D.; Dyer, M. J. S.; Cohen, G. M. (March 2009). "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy". Cell Death & Differentiation 16 (3): 360–367. doi:10.1038/cdd.2008.137. PMID 18806758. 
  20. ↑ "An inhibitor of Bcl-2 family proteins induces regression of solid tumours". Nature 435 (7042): 677–81. June 2005. doi:10.1038/nature03579. PMID 15902208. Bibcode: 2005Natur.435..677O. 
  21. ↑ "Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer". Cancer Research 68 (7): 2321–8. April 2008. doi:10.1158/0008-5472.can-07-5031. PMID 18381439. 
  22. ↑ Hauck, P.; Chao, B. H.; Litz, J.; Krystal, G. W. (1 April 2009). "Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737". Molecular Cancer Therapeutics 8 (4): 883–892. doi:10.1158/1535-7163.MCT-08-1118. PMID 19372561. 
  23. ↑ "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 29 (7): 909–16. March 2011. doi:10.1200/JCO.2010.31.6208. PMID 21282543. 
  24. ↑ "Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer". Clinical Cancer Research 18 (11): 3163–9. June 2012. doi:10.1158/1078-0432.CCR-11-3090. PMID 22496272. 
  25. ↑ "Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia". Cancer Chemotherapy and Pharmacology 74 (3): 593–602. September 2014. doi:10.1007/s00280-014-2530-9. PMID 25053389. 
  26. ↑ "Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia". Cancer Discovery 4 (3): 362–75. March 2014. doi:10.1158/2159-8290.CD-13-0609. PMID 24346116. 
  27. ↑ Liao, Grace (12 August 2011). "ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia". Asian Scientist. http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia. 
  28. ↑ 28.0 28.1 "Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia". The New England Journal of Medicine 374 (4): 311–22. January 2016. doi:10.1056/NEJMoa1513257. PMID 26639348. 
  29. ↑ "'Miracle drug cured my cancer!': Amazing three-week recovery of Staffordshire sufferer". Stoke Sentinel. http://www.stokesentinel.co.uk/Miracle-drug-cured-cancer-Amazing-recovery/story-21080535-detail/story.html. 
  30. ↑ Smith, Michael (7 December 2015). "Hard-to-Treat CLL Yields to Investigational Drug". http://www.medpagetoday.com/MeetingCoverage/ASHHematology/55056. 
  31. ↑ 31.0 31.1 Bankhead, Charles (11 April 2016). "FDA Approves AbbVie's BCL-2 Targeting Drug for CLL" (in en). Medpage Today. https://www.medpagetoday.com/hematologyoncology/leukemia/57298. 
  32. ↑ "FDA approves venetoclax for CLL or SLL, with or without 17p deletion, after one prior therapy" (in en). U.S. Food and Drug Administration. 24 March 2020. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. 
  33. ↑ 33.0 33.1 33.2 33.3 "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell 116 (4): 527–40. Feb 2004. doi:10.1016/s0092-8674(04)00162-x. PMID 14980220. 
  34. ↑ "Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening". Journal of Medicinal Chemistry 44 (25): 4313–24. Dec 2001. doi:10.1021/jm010016f. PMID 11728179. 
  35. ↑ "p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum". The Journal of Cell Biology 139 (2): 327–38. Oct 1997. doi:10.1083/jcb.139.2.327. PMID 9334338. 
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  37. ↑ 37.0 37.1 37.2 37.3 37.4 37.5 "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Molecular Cell 17 (3): 393–403. Feb 2005. doi:10.1016/j.molcel.2004.12.030. PMID 15694340. 
  38. ↑ "Bim: a novel member of the Bcl-2 family that promotes apoptosis". The EMBO Journal 17 (2): 384–95. Jan 1998. doi:10.1093/emboj/17.2.384. PMID 9430630. 
  39. ↑ "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". Molecular Endocrinology 12 (9): 1432–40. Sep 1998. doi:10.1210/mend.12.9.0166. PMID 9731710. 
  40. ↑ "Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein". Journal of Virology 72 (11): 8586–96. Nov 1998. doi:10.1128/JVI.72.11.8586-8596.1998. PMID 9765397. 
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  42. ↑ "Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis". Science 293 (5536): 1829–32. Sep 2001. doi:10.1126/science.1062257. PMID 11546872. Bibcode: 2001Sci...293.1829P. 
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  44. ↑ 44.0 44.1 "Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins". Cell 79 (2): 341–51. Oct 1994. doi:10.1016/0092-8674(94)90202-X. PMID 7954800. 
  45. ↑ "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". The Journal of Biological Chemistry 275 (2): 1439–48. Jan 2000. doi:10.1074/jbc.275.2.1439. PMID 10625696. 
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  48. ↑ 48.0 48.1 "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nature Cell Biology 2 (1): 1–6. Jan 2000. doi:10.1038/71316. PMID 10620799. 
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  51. ↑ "Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway". The EMBO Journal 22 (14): 3580–90. Jul 2003. doi:10.1093/emboj/cdg343. PMID 12853473. 
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  55. ↑ "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". The Journal of Biological Chemistry 277 (16): 13430–7. Apr 2002. doi:10.1074/jbc.M108029200. PMID 11832478. 
  56. ↑ "Microtubule-targeting drugs induce bcl-2 phosphorylation and association with Pin1". Neoplasia 3 (6): 550–9. 2001. doi:10.1038/sj.neo.7900213. PMID 11774038. 
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  63. ↑ "Presenilin 1 protein directly interacts with Bcl-2". The Journal of Biological Chemistry 274 (43): 30764–9. Oct 1999. doi:10.1074/jbc.274.43.30764. PMID 10521466. 
  64. ↑ "Bcl-2 associates with the ras-related protein R-ras p23". Nature 366 (6452): 274–5. Nov 1993. doi:10.1038/366274a0. PMID 8232588. Bibcode: 1993Natur.366..274F. 
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  66. ↑ "Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy". Nature 390 (6658): 413–7. Nov 1997. doi:10.1038/37144. PMID 9389483. Bibcode: 1997Natur.390..413I. 
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