• negative regulation of neuron apoptotic process • intrinsic apoptotic signaling pathway in response to oxidative stress • ureteric bud development • renal system process • organ growth • T cell differentiation in thymus • lymphocyte homeostasis • response to steroid hormone • positive regulation of catalytic activity • ear development • glomerulus development • post-embryonic development • cellular response to DNA damage stimulus • T cell homeostasis • negative regulation of ossification • negative regulation of G1/S transition of mitotic cell cycle • positive regulation of smooth muscle cell migration • regulation of protein localization • cell aging • T cell differentiation • B cell lineage commitment • response to ischemia • regulation of mitochondrial membrane permeability • humoral immune response • defense response to virus • mesenchymal cell development • positive regulation of multicellular organism growth • animal organ morphogenesis • developmental pigmentation • hair follicle morphogenesis • B cell differentiation • cell proliferation • metanephros development • melanocyte differentiation • negative regulation of autophagy • positive regulation of neuron maturation • negative regulation of myeloid cell apoptotic process • cellular response to hypoxia • pigment granule organization • negative regulation of cell proliferation • B cell receptor signaling pathway • cellular response to organic substance • regulation of apoptotic process • response to cytokine • cellular response to glucose starvation • regulation of protein stability • ossification • positive regulation of melanocyte differentiation • axon regeneration • kidney development • actin filament organization • thymus development • negative regulation of intrinsic apoptotic signaling pathway • negative regulation of apoptotic signaling pathway • response to nicotine • spleen development • endoplasmic reticulum calcium ion homeostasis • positive regulation of skeletal muscle fiber development • response to oxidative stress • lymphoid progenitor cell differentiation • positive regulation of peptidyl-serine phosphorylation • CD8-positive, alpha-beta T cell lineage commitment • reactive oxygen species metabolic process • negative regulation of retinal cell programmed cell death • branching involved in ureteric bud morphogenesis • gland morphogenesis • positive regulation of cell growth • positive regulation of B cell proliferation • negative regulation of cell growth • response to gamma radiation • positive regulation of intrinsic apoptotic signaling pathway • response to toxic substance • digestive tract morphogenesis • neuron apoptotic process • male gonad development • regulation of protein heterodimerization activity • regulation of glycoprotein biosynthetic process • regulation of viral genome replication • female pregnancy • negative regulation of mitochondrial depolarization • protein dephosphorylation • protein polyubiquitination • cellular calcium ion homeostasis • B cell homeostasis • behavioral fear response • oocyte development • regulation of cell-matrix adhesion • response to iron ion • negative regulation of cell migration • regulation of autophagy • positive regulation of developmental pigmentation • developmental growth • regulation of transmembrane transporter activity • ovarian follicle development • regulation of gene expression • negative regulation of calcium ion transport into cytosol • negative regulation of osteoblast proliferation • homeostasis of number of cells within a tissue • pigmentation • response to radiation • regulation of catalytic activity • peptidyl-threonine phosphorylation • regulation of protein homodimerization activity • negative regulation of anoikis • response to hydrogen peroxide • T cell lineage commitment • cochlear nucleus development • leukocyte homeostasis • regulation of programmed cell death • regulation of calcium ion transport • axonogenesis • negative regulation of cellular pH reduction • response to glucocorticoid • regulation of cell cycle • regulation of mitochondrial membrane potential • melanin metabolic process • focal adhesion assembly • positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway • B cell proliferation • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • immune system development • apoptotic mitochondrial changes • peptidyl-serine phosphorylation • regulation of nitrogen utilization • cell morphogenesis • positive regulation of cell proliferation • negative regulation of reactive oxygen species metabolic process • response to UV-B • regulation of developmental pigmentation • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand • extrinsic apoptotic signaling pathway via death domain receptors • response to drug • release of cytochrome c from mitochondria • negative regulation of mitotic cell cycle • extrinsic apoptotic signaling pathway in absence of ligand • apoptotic process • transmembrane transport • intrinsic apoptotic signaling pathway in response to DNA damage • growth • cell-cell adhesion • cytokine-mediated signaling pathway • negative regulation of apoptotic process • haematopoiesis • regulation of growth • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
596
12043
Ensembl
ENSG00000171791
ENSMUSG00000057329
UniProt
P10415
P10417
RefSeq (mRNA)
NM_000633 NM_000657
NM_009741 NM_177410
RefSeq (protein)
NP_000624 NP_000648
NP_033871 NP_803129
Location (UCSC)
Chr 18: 63.12 – 63.32 Mb
Chr 1: 106.54 – 106.71 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
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.[5][6]
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[7] (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.
Contents
1Isoforms
2Normal physiological function
3Role in disease
3.1Cancer
3.2Auto-immune diseases
3.3Other
4Diagnostic use
5Targeted therapies
5.1Oblimersen
5.2ABT-737 and navitoclax (ABT-263)
5.3Venetoclax (ABT-199)
6Interactions
7See also
8References
9External links
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.[8]
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.[9]
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,[10] but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.[11]
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.[12] 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.[13] 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.[14] 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.[14] Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.[14]
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.[15] Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[15]
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.[16]
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.[17]
These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.[18] As of 2016, the drug had not been approved and its developer was out of business.[19]
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.[20] 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.[21] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.[22] 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.[23] While clinical responses with navitoclax were promising, mechanistic dose-limiting thrombocytopoenia was observed in patients under treatment due to Bcl-xL inhibition in platelets.[24][25][26]
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.[27] 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).[28][29] Good responses have been reported and thrombocytopoenia was no longer observed.[29][30] A phase 3 trial started in Dec 2015.[31]
It was approved by the US FDA in April 2016 as a second-line treatment for CLL associated with 17-p deletion.[32] This was the first FDA approval of a BCL-2 inhibitor.[32] 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.[33]
Interactions
Overview of signal transduction pathways involved in apoptosis.
Bcl-2 has been shown to interact with:
BAK1,[34][35]
BCAP31,[36]
BCL2-like 1,[34][37]
BCL2L11,[38][39][40]
BECN1,[41]
BID,[38][42]
BMF,[43]
BNIP2,[44][45]
BNIP3,[45][46]
BNIPL,[44][47]
BAD[38][48]
BAX,[34][49][50][51]
BIK,[38][52]
C-Raf,[53]
CAPN2,[54]
CASP8,[55][56]
Cdk1,[57][58]
HRK,[38][59]
IRS1,[60]
Myc,[61]
NR4A1,[34]
Noxa,[38][62]
PPP2CA,[63]
PSEN1,[64]
RAD9A,[49]
RRAS,[65]
RTN4,[66]
SMN1,[67]
SOD1,[68] and
TP53BP2.[69]
See also
Apoptosis
Apoptosome
Bcl-2 homologous antagonist killer (BAK)
Bcl-2-associated X protein (BAX)
Bcl-xL
BH3 interacting domain death agonist (BID)
Caspases
Cytochrome c
Noxa
Mcl-1
Mitochondrion
Microphthalmia-associated transcription factor
Protein mimetic
p53 upregulated modulator of apoptosis (PUMA)
Senolytics
References
^ abcGRCh38: Ensembl release 89: ENSG00000171791 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000057329 - Ensembl, May 2017
^"Human PubMed Reference:".
^"Mouse PubMed Reference:".
^Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (November 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.
^Cleary ML, Smith SD, Sklar J (October 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.
^"OrthoMaM phylogenetic marker: Bcl-2 coding sequence". Archived from the original on 24 September 2015. Retrieved 20 December 2009.
^PDB: 1G5M; Petros AM, Medek A, Nettesheim DG, Kim DH, Yoon HS, Swift K, Matayoshi ED, Oltersdorf T, Fesik SW (March 2001). "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. doi:10.1073/pnas.041619798. PMID 11248023.
^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.
^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.
^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. PMID 27070098.
^Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ (April 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.
^Vaux DL, Cory S, Adams JM (September 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.
^ abcLi 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.
^ abGlantz LA, Gilmore JH, Lieberman JA, Jarskog LF (January 2006). "Apoptotic mechanisms and the synaptic pathology of schizophrenia". Schizophrenia Research. 81 (1): 47–63. doi:10.1016/j.schres.2005.08.014. PMID 16226876.
^Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. XX. ISBN 978-1-84110-100-2.
^Dias N, Stein CA (November 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.
^"Genasense (oblimersen sodium) FDA Approval Status - Drugs.com". www.drugs.com. Retrieved 11 February 2016.
^Vogler, Meike, et al. "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy." Cell Death & Differentiation 16.3 (2008): 360–367.
^Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. (June 2005). "An inhibitor of Bcl-2 family proteins induces regression of solid tumours". Nature. 435 (7042): 677–81. Bibcode:2005Natur.435..677O. doi:10.1038/nature03579. PMID 15902208.
^Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM (April 2008). "Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer". Cancer Research. 68 (7): 2321–8. doi:10.1158/0008-5472.can-07-5031. PMC 3159963. PMID 18381439.
^"Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737".[permanent dead link]
^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 (March 2011). "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. doi:10.1200/JCO.2010.31.6208. PMC 4668282. PMID 21282543.
^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 (June 2012). "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. doi:10.1158/1078-0432.CCR-11-3090. PMC 3715059. PMID 22496272.
^Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H (September 2014). "Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia". Cancer Chemotherapy and Pharmacology. 74 (3): 593–602. doi:10.1007/s00280-014-2530-9. PMID 25053389.
^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 (March 2014). "Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia". Cancer Discovery. 4 (3): 362–75. doi:10.1158/2159-8290.CD-13-0609. PMC 3975047. PMID 24346116.
^Liao G (12 August 2011). "ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia". Asian Scientist. Archived from the original on 18 July 2012. Retrieved February 11, 2016.
^ abRoberts 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 (January 2016). "Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia". The New England Journal of Medicine. 374 (4): 311–22. doi:10.1056/NEJMoa1513257. PMID 26639348.
^"'Miracle drug cured my cancer!': Amazing three-week recovery of Staffordshire sufferer". Stoke Sentinel. Archived from the original on 12 May 2014. Retrieved 10 May 2014.
^Smith M (7 December 2015). "Hard-to-Treat CLL Yields to Investigational Drug".
^ abBankhead C (11 April 2016). "FDA Approves AbbVie's BCL-2 Targeting Drug for CLL". Medpage Today.
^"FDA approves venetoclax for CLL or SLL, with or without 17p deletion, after one prior therapy". U.S. Food and Drug Administration.
^ abcdLin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK (February 2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell. 116 (4): 527–40. doi:10.1016/s0092-8674(04)00162-x. PMID 14980220.
^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 (December 2001). "Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening". Journal of Medicinal Chemistry. 44 (25): 4313–24. doi:10.1021/jm010016f. PMID 11728179.
^Ng FW, Nguyen M, Kwan T, Branton PE, Nicholson DW, Cromlish JA, Shore GC (October 1997). "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. doi:10.1083/jcb.139.2.327. PMC 2139787. PMID 9334338.
^Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (August 2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Analytical Biochemistry. 307 (1): 70–5. doi:10.1016/s0003-2697(02)00028-3. PMID 12137781.
^ abcdefChen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (February 2005). "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function". Molecular Cell. 17 (3): 393–403. doi:10.1016/j.molcel.2004.12.030. PMID 15694340.
^O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC (January 1998). "Bim: a novel member of the Bcl-2 family that promotes apoptosis". The EMBO Journal. 17 (2): 384–95. doi:10.1093/emboj/17.2.384. PMC 1170389. PMID 9430630.
^Hsu SY, Lin P, Hsueh AJ (September 1998). "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. doi:10.1210/mend.12.9.0166. PMID 9731710.
^Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B (November 1998). "Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein". Journal of Virology. 72 (11): 8586–96. PMC 110269. PMID 9765397.
^Real PJ, Cao Y, Wang R, Nikolovska-Coleska Z, Sanz-Ortiz J, Wang S, Fernandez-Luna JL (November 2004). "Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2". Cancer Research. 64 (21): 7947–53. doi:10.1158/0008-5472.CAN-04-0945. PMID 15520201.
^Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A (September 2001). "Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis". Science. 293 (5536): 1829–32. Bibcode:2001Sci...293.1829P. doi:10.1126/science.1062257. PMID 11546872.
^ abQin W, Hu J, Guo M, Xu J, Li J, Yao G, Zhou X, Jiang H, Zhang P, Shen L, Wan D, Gu J (August 2003). "BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis". Biochemical and Biophysical Research Communications. 308 (2): 379–85. doi:10.1016/s0006-291x(03)01387-1. PMID 12901880.
^ abBoyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G (October 1994). "Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins". Cell. 79 (2): 341–51. doi:10.1016/0092-8674(94)90202-X. PMID 7954800.
^Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Gietz RD, Greenberg AH (January 2000). "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. doi:10.1074/jbc.275.2.1439. PMID 10625696.
^Yasuda M, Han JW, Dionne CA, Boyd JM, Chinnadurai G (February 1999). "BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3". Cancer Research. 59 (3): 533–7. PMID 9973195.
^Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (January 1995). "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death". Cell. 80 (2): 285–91. doi:10.1016/0092-8674(95)90411-5. PMID 7834748.
^ abKomatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG (January 2000). "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nature Cell Biology. 2 (1): 1–6. doi:10.1038/71316. PMID 10620799.
^Hoetelmans RW (June 2004). "Nuclear partners of Bcl-2: Bax and PML". DNA and Cell Biology. 23 (6): 351–4. doi:10.1089/104454904323145236. PMID 15231068.
^Oltvai ZN, Milliman CL, Korsmeyer SJ (August 1993). "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death". Cell. 74 (4): 609–19. doi:10.1016/0092-8674(93)90509-O. PMID 8358790.
^Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT (July 2003). "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. doi:10.1093/emboj/cdg343. PMC 165613. PMID 12853473.
^Wang HG, Rapp UR, Reed JC (November 1996). "Bcl-2 targets the protein kinase Raf-1 to mitochondria". Cell. 87 (4): 629–38. doi:10.1016/s0092-8674(00)81383-5. PMID 8929532.
^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 (July 2002). "Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members". The Journal of Biological Chemistry. 277 (30): 27217–26. doi:10.1074/jbc.M202945200. PMID 12000759.
^Poulaki V, Mitsiades N, Romero ME, Tsokos M (June 2001). "Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2". Cancer Research. 61 (12): 4864–72. PMID 11406564.
^Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (April 2002). "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". The Journal of Biological Chemistry. 277 (16): 13430–7. doi:10.1074/jbc.M108029200. PMID 11832478.
^Pathan N, Aime-Sempe C, Kitada S, Basu A, Haldar S, Reed JC (2001). "Microtubule-targeting drugs induce bcl-2 phosphorylation and association with Pin1". Neoplasia. 3 (6): 550–9. doi:10.1038/sj.neo.7900213. PMC 1506558. PMID 11774038.
^Pathan N, Aime-Sempe C, Kitada S, Haldar S, Reed JC (2001). "Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1". Neoplasia. 3 (1): 70–9. doi:10.1038/sj.neo.7900131. PMC 1505024. PMID 11326318.
^Inohara N, Ding L, Chen S, Núñez G (April 1997). "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)". The EMBO Journal. 16 (7): 1686–94. doi:10.1093/emboj/16.7.1686. PMC 1169772. PMID 9130713.
^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 (February 2000). "Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function". Molecular Biology of the Cell. 11 (2): 735–46. doi:10.1091/mbc.11.2.735. PMC 14806. PMID 10679027.
^Jin Z, Gao F, Flagg T, Deng X (September 2004). "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". The Journal of Biological Chemistry. 279 (38): 40209–19. doi:10.1074/jbc.M404056200. PMID 15210690.
^Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N (May 2000). "Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis". Science. 288 (5468): 1053–8. Bibcode:2000Sci...288.1053O. doi:10.1126/science.288.5468.1053. PMID 10807576.
^Deng X, Ito T, Carr B, Mumby M, May WS (December 1998). "Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A". The Journal of Biological Chemistry. 273 (51): 34157–63. doi:10.1074/jbc.273.51.34157. PMID 9852076.
^Alberici A, Moratto D, Benussi L, Gasparini L, Ghidoni R, Gatta LB, Finazzi D, Frisoni GB, Trabucchi M, Growdon JH, Nitsch RM, Binetti G (October 1999). "Presenilin 1 protein directly interacts with Bcl-2". The Journal of Biological Chemistry. 274 (43): 30764–9. doi:10.1074/jbc.274.43.30764. PMID 10521466.
^Fernandez-Sarabia MJ, Bischoff JR (November 1993). "Bcl-2 associates with the ras-related protein R-ras p23". Nature. 366 (6452): 274–5. Bibcode:1993Natur.366..274F. doi:10.1038/366274a0. PMID 8232588.
^Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y (November 2000). "A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity". Oncogene. 19 (50): 5736–46. doi:10.1038/sj.onc.1203948. PMID 11126360.
^Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y (November 1997). "Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy". Nature. 390 (6658): 413–7. Bibcode:1997Natur.390..413I. doi:10.1038/37144. PMID 9389483.
^Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH (July 2004). "Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria". Neuron. 43 (1): 19–30. doi:10.1016/j.neuron.2004.06.021. PMID 15233914.
^Naumovski L, Cleary ML (July 1996). "The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M". Molecular and Cellular Biology. 16 (7): 3884–92. doi:10.1128/MCB.16.7.3884. PMC 231385. PMID 8668206.
External links
The Bcl-2 Family Database
The Bcl-2 Family at celldeath.de
Bcl-2 publications sorted by impact at caspases.org
bcl-2+Genes at the US National Library of Medicine Medical Subject Headings (MeSH)
c-bcl-2+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
Human BCL2 genome location and BCL2 gene details page in the UCSC Genome Browser.
v
t
e
Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes
Ligand
Growth factors
ONCO
c-Sis/PDGF
HGF
Receptor
Wnt signaling pathway
TSP
CDH1
Hedgehog signaling pathway
TSP
PTCH1
TGF beta signaling pathway
TSP
TGF beta receptor 2
Receptor tyrosine kinase
ONCO
ErbB/c-ErbB
HER2/neu
Her 3
c-Met
c-Ret
JAK-STAT signaling pathway
ONCO
c-Kit
Flt3
Intracellular signaling P+Ps
Wnt signaling pathway
ONCO
Beta-catenin
TSP
APC
TGF beta signaling pathway
TSP
SMAD2
SMAD4
Akt/PKB signaling pathway
ONCO
c-Akt
TSP
PTEN
Hippo signaling pathway
TSP
Neurofibromin 2/Merlin
MAPK/ERK pathway
ONCO
c-Ras
HRAS
c-Raf
TSP
Neurofibromin 1
Other/unknown
ONCO
c-Src
TSP
Maspin
Nucleus
Cell cycle
ONCO
CDK4
Cyclin D
Cyclin E
TSP
p53
pRb
WT1
p16/p14arf
DNA repair/Fanconi
TSP
BRCA1
BRCA2
Ubiquitin ligase
ONCO
CBL
MDM2
TSP
VHL
Transcription factor
ONCO
AP-1
c-Fos
c-Jun
c-Myc
TSP
KLF6
Mitochondrion
Apoptosis inhibitor
SDHB
SDHD
Other/ungrouped
c-Bcl-2
Notch
Stathmin
v
t
e
Apoptosis signaling pathway
Fas path
Ligand
Fas ligand
Receptor
Fas receptor
Intracellular
Death-inducing signaling complex
DAXX
ASK1
FADD
Caspase 8
BID
Cytochrome c
Caspase 9
Caspase 3
Pro-apoptotic:
BAX
BAK1/Bcl-2 homologous antagonist killer
Bcl-2-associated death promoter
Anti-apoptotic:
Bcl-2
Bcl-xL
TNF path
Ligand
Tumor necrosis factor alpha
Receptor
Tumor necrosis factor receptor 1
Tumor necrosis factor receptor 2
Intracellular
TRADD
FADD
Caspase 8
Caspase 3
BID
TRAF2
ASK-1
MEKK1
IKK
IκBα
MKK7
JNK
NF-κB
Other
Intracellular
IAPs
XIAP
NAIP
Survivin
c-IAP-1
c-IAP-2
Apoptosis-inducing factor
UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
…leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21. BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in prolonged cell survival. BCL-2 overexpression …
…leukemia/lymphoma 2 (BCL2) is an oncogene that blocks programmed cell death (apoptosis), leading to prolonged cell survival. BCL2 overexpression is often the result of a (14;18) translocation that places BCL2 under the …
…in AML . BCL-2 (B cell leukemia/lymphoma-2) is overexpressed in a wide variety of lymphoid malignancies as a result of t(14;18), which juxtaposes BCL-2 with the Ig heavy chain locus. BCL-2 overexpression …
…of the head and neck region; Predominance of grade 3 histology; Absence of BCL2 rearrangements and infrequent presence of BCL-2 protein expression (approximately 30 percent) The presence of activating …
…a t(14;18) chromosomal translocation in which the BCL2 gene at 18q21 is placed into juxtaposition with the Ig heavy-chain locus at 14q32 . However, BCL2 expression is elevated in approximately 95 percent …
English Journal
6-Gingerol protects cardiocytes H9c2 against hypoxia-induced injury by suppressing BNIP3 expression.
Ren Q, Zhao S, Ren C.
Artificial cells, nanomedicine, and biotechnology. 2019 Dec;47(1)2016-2023.
Long non-coding RNA ROR mitigates cobalt chloride-induced hypoxia injury through regulation of miR-145.
Ge H, Liu J, Liu F, Sun Y, Yang R.
Artificial cells, nanomedicine, and biotechnology. 2019 Dec;47(1)2221-2229.
Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is a condition causing apnea and hypopnea. LncRNA-ROR revealed properties in regulating hypoxia response. Our study explored the roles of ROR in CoCl-induced hypoxia injury in HK-2 cells. HK-2 cells were treated with CoCl to induce hypoxia injury.
Du Xing-Xu,Tao Xue,Liang Shuang,Che Jin-Ying,Yang Shuo,Li He,Chen Jian-Guang,Wang Chun-Mei
Ｂｉｏｌｏｇｉｃａｌ ＆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ, 2019
… </i>Type 2 diabetic (T2D) rats were developed by giving a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), and administered orally with SCAP (25, 50 mg/kg) for 8 weeks. … Furthermore, expressions of c-Jun N-terminal kinase (JNK), B-cell lymphoma 2-associated X protein (BAX), B-cell lymphoma 2 (Bcl-2), and Cleaved Caspase-3 in pancreatic islet were detected. …