BCL2, apoptosis regulator

Target id: 2844

Nomenclature: BCL2, apoptosis regulator

Abbreviated Name: Bcl-2

Family: B-cell lymphoma 2 (Bcl-2) protein family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     BCL2, apoptosis regulator has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 239 18q21.3 BCL2 BCL2, apoptosis regulator
Mouse - 236 1 E2.1 Bcl2 B cell leukemia/lymphoma 2
Rat - 236 13p13 Bcl2 BCL2, apoptosis regulator
Previous and Unofficial Names
B-cell CLL/lymphoma 2
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Bcl_2-Navitoclax (ABT-263) Complex.
PDB Id:  4LVT
Ligand:  navitoclax
Resolution:  2.05Å
Species:  Human
References:  10

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Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
venetoclax Hs Antagonist >11.0 pKi 4,10
pKi >11.0 (Ki <1x10-11 M) [4,10]
Description: Note that this Ki is below the detection limit of the assay.
navitoclax Hs Antagonist >9.0 pKi 9
pKi >9.0 (Ki <1x10-9 M) [9]
ABT-737 Hs Antagonist >9.0 pKi 2
pKi >9.0 (Ki <1x10-9 M) [2]
Immunopharmacology Comments
The role of Bcl-2 family members in immunity and disease is reviewed in [5]. Pharmacological inhibition of Bcl-2 family proteins reduces disease severity in several animal models of autoimmunity; see ligand ABT-737 [1].
Immuno Process Associations
Immuno Process:  B cell (activation)
Immuno Process ID:  5
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  B cell lineage commitment (GO:0002326) IEA
positive regulation of B cell proliferation (GO:0030890) IMP
B cell proliferation (GO:0042100) IDA
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  B cell homeostasis (GO:0001782) IEA
positive regulation of B cell proliferation (GO:0030890) IMP
T cell homeostasis (GO:0043029) IEA
B cell receptor signaling pathway (GO:0050853) IMP
References: 
Immuno Process:  Cytokine production & signalling
Immuno Process ID:  9
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  response to cytokine (GO:0034097) IDA
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  protein polyubiquitination (GO:0000209) IDA
B cell lineage commitment (GO:0002326) IEA
positive regulation of B cell proliferation (GO:0030890) IMP
T cell differentiation in thymus (GO:0033077) IEA
B cell proliferation (GO:0042100) IDA
CD8-positive, alpha-beta T cell lineage commitment (GO:0043375) IEA
B cell receptor signaling pathway (GO:0050853) IMP
References: 
Immuno Process:  T cell (activation)
Immuno Process ID:  4
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  T cell differentiation in thymus (GO:0033077) IEA
CD8-positive, alpha-beta T cell lineage commitment (GO:0043375) IEA
References: 
Immuno Process:  Immune system development
Immuno Process ID:  8
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  lymphoid progenitor cell differentiation (GO:0002320) IEA
B cell lineage commitment (GO:0002326) IEA
T cell differentiation in thymus (GO:0033077) IEA
CD8-positive, alpha-beta T cell lineage commitment (GO:0043375) IEA
spleen development (GO:0048536) IEA
thymus development (GO:0048538) IEA
References: 
General Comments
Bcl-2 is an anti-apoptotic (prosurvival) protein with oncogenic actions which was originally identified in chromosomal translocations in follicular lymphoma cells [11]. Abnormal expression of Bcl-2 de-stabilises the balance between pro- and anti-apoptotic signals, driving the homeostatic balance between cell growth and cell death towards growth. The role of Bcl-2 in cancers and other important conditions (for example autoimmune diseases and schizophrenia) makes it an attractive target for pharmaceutical intervention. The first Bcl-2 antagonist to be approved for clinical use is (ABT-199) [4]. Another small molecule inhibitor, (ABT-263) [9], is in also developement for chronic lymphocytic leukemia (CLL) and other blood cancers. A Bcl-2 antinsense oligonucleotide was assessed in lymphoma [3,7] and [6,8] was investigated as a breast and ovarian cancer therapy.

References

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1. Bardwell PD, Gu J, McCarthy D, Wallace C, Bryant S, Goess C, Mathieu S, Grinnell C, Erickson J, Rosenberg SH et al.. (2009) The Bcl-2 family antagonist ABT-737 significantly inhibits multiple animal models of autoimmunity. J. Immunol.182 (12): 7482-9. [PMID:19494271]

2. Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC et al.. (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J. Med. Chem.50 (4): 641-62. [PMID:17256834]

3. Dias N, Stein CA. (2002) Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm54 (3): 263-9. [PMID:12445555]

4. Doherty GA, Elmore SW, Hasvold LA, Souers AJ, Tao Z-F, Wang GT, Wang L, Mantei R, Hansen TM. (2013) Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases. Patent number: US8580794. Assignee: Abbvie Inc.. Priority date: 26/05/2009. Publication date: 12/11/2013.

5. Droin NM, Green DR. (2004) Role of Bcl-2 family members in immunity and disease. Biochim. Biophys. Acta1644 (2-3): 179-88. [PMID:14996502]

6. Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, Hosui A, Miyagi T, Tatsumi T, Ishida H et al.. (2010) The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology52 (4): 1310-21. [PMID:20799354]

7. Mavromatis BH, Cheson BD. (2004) Novel therapies for chronic lymphocytic leukemia. Blood Rev.18 (2): 137-48. [PMID:15010151]

8. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ et al.. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature435 (7042): 677-81. [PMID:15902208]

9. Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X et al.. (2008) Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J. Med. Chem.51 (21): 6902-15. [PMID:18841882]

10. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ et al.. (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med.19 (2): 202-8. [PMID:23291630]

11. Vaux DL, Cory S, Adams JM. (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature335 (6189): 440-2. [PMID:3262202]

How to cite this page

B-cell lymphoma 2 (Bcl-2) protein family: BCL2, apoptosis regulator. Last modified on 31/01/2017. Accessed on 20/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2844.