“Bcl-2”的意思、由来-开放百科全书

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

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|date=June 2016}}

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 psychiatric disorder in which an abnormal ratio of pro- and anti-apoptotic factors may contribute towards pathogenesis.^[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 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.^[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|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.^[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 as a second-line treatment for CLL associated with 17-p deletion.^[28] This was the first FDA approval of a BCL-2 inhibitor.^[28] 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.^[29]

Interactions

See also

References

1. ^{{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 }}
2. ^{{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 }}
3. ^{{cite web | title = OrthoMaM phylogenetic marker: Bcl-2 coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000171791_BCL2.xml }}
4. ^{{cite journal | title = Human Bcl2, Isoform 1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | pages = 3012–3017 | url = http://www.rcsb.org/pdb/explore/explore.do?structureId=1G5M | doi = 10.2210/pdb1g5m/pdb | year = 2001 | last1 = Petros | first1 = A.M. | last2 = Medek | first2 = A. | last3 = Nettesheim | first3 = D.G. | last4 = Kim | first4 = D.H. | last5 = Yoon | first5 = H.S. | last6 = Swift | first6 = K. | last7 = Matayoshi | first7 = E.D. | last8 = Oltersdorf | first8 = T. | last9 = Fesik | first9 = S.W. }}
5. ^{{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}}
6. ^{{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}}
7. ^{{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}}
8. ^{{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 }}
9. ^{{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 }}
10. ^¹²{{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 }}
11. ^¹{{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 }}
12. ^{{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=978-1-84110-100-2}}
13. ^{{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 }}
14. ^{{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 }}
15. ^{{Cite web|title = Genasense (oblimersen sodium) FDA Approval Status - Drugs.com|url = https://www.drugs.com/history/genasense.html|website = www.drugs.com|access-date = 2016-02-11}}
16. ^Vogler, Meike, et al. "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy." Cell Death & Differentiation 16.3 (2008): 360–367.
17. ^{{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 | display-authors = 6 | title = An inhibitor of Bcl-2 family proteins induces regression of solid tumours | journal = Nature | volume = 435 | issue = 7042 | pages = 677–81 | date = June 2005 | pmid = 15902208 | doi = 10.1038/nature03579 | bibcode = 2005Natur.435..677O }}
18. ^{{cite journal | vauthors = Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM | title = Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer | journal = Cancer Research | volume = 68 | issue = 7 | pages = 2321–8 | date = April 2008 | pmid = 18381439 | pmc = 3159963 | doi = 10.1158/0008-5472.can-07-5031 }}
19. ^{{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=}}{{Dead link|date=November 2018 |bot=InternetArchiveBot |fix-attempted=yes }}
20. ^{{cite journal | vauthors = Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM | 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 | volume = 29 | issue = 7 | pages = 909–16 | date = March 2011 | pmid = 21282543 | pmc = 4668282 | doi = 10.1200/JCO.2010.31.6208 }}
21. ^{{cite journal | vauthors = Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L | 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 = 3163–9 | date = June 2012 | pmid = 22496272 | pmc = 3715059 | doi = 10.1158/1078-0432.CCR-11-3090 }}
22. ^{{cite journal | vauthors = Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H | 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 | date = September 2014 | pmid = 25053389 | doi = 10.1007/s00280-014-2530-9 }}
23. ^{{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 = 362–75 | date = March 2014 | pmid = 24346116 | pmc = 3975047 | doi = 10.1158/2159-8290.CD-13-0609 }}
24. ^{{cite news |title=ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia |first=Grace |last=Liao | name-list-format = vanc |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 |access-date=February 11, 2016 |deadurl=yes |archive-url=https://web.archive.org/web/20120718151431/http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia/ |archive-date=18 July 2012 |df=dmy }}
25. ^¹{{cite journal | vauthors = Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF | title = Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia | journal = The New England Journal of Medicine | volume = 374 | issue = 4 | pages = 311–22 | date = January 2016 | pmid = 26639348 | doi = 10.1056/NEJMoa1513257 }}
26. ^{{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|access-date=10 May 2014|archive-url=https://web.archive.org/web/20140512200023/http://www.stokesentinel.co.uk/Miracle-drug-cured-cancer-Amazing-recovery/story-21080535-detail/story.html|archive-date=12 May 2014|dead-url=yes|df=dmy-all}}
27. ^{{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=}}
28. ^¹{{cite news |last1=Bankhead |first1=Charles | name-list-format = vanc |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}}
29. ^{{cite web|title=FDA approves venetoclax for CLL or SLL, with or without 17p deletion, after one prior therapy|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm|publisher=U.S. Food and Drug Administration|language=en}}
30. ^¹²³{{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 }}
31. ^{{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 }}
32. ^{{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 }}
33. ^{{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 }}
34. ^{{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 }}
35. ^{{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 }}
36. ^{{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 = }}
37. ^{{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 }}
38. ^{{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 }}
39. ^¹{{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 }}
40. ^{{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 }}
41. ^¹{{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 }}
42. ^{{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 = }}
43. ^{{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 }}
44. ^{{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 }}
45. ^{{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 }}
46. ^¹²³⁴⁵{{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 }}
47. ^{{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 }}
48. ^{{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 }}
49. ^{{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 }}
50. ^{{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 = }}
51. ^{{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 }}
52. ^{{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 }}
53. ^{{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 }}
54. ^{{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 }}
55. ^{{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 }}
56. ^{{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 }}
57. ^{{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 }}
58. ^{{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 }}
59. ^{{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 }}
60. ^¹{{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 }}
61. ^{{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 }}
62. ^{{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 }}
63. ^{{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 }}
64. ^{{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 }}
65. ^{{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 = 10.1128/MCB.16.7.3884}}