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B-cell leukemia-2 (bcl-2) protein

Function: - suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic & neural cells - Bcl-2 prevents apoptosis triggered by various death stimuli including growth factor deprivation, radiation, cytotoxic chemotherapy, & in some cases Fas activation - cytotoxic T-cell mediated apoptosis is resistant to bcl-2 [5] - regulates cell death by controlling mitochondrial membrane permeability - appears to function in a feedback loop system with caspases - inhibits caspase activity either by preventing the release of cytochrome c from mitochondria &/or by binding to the apoptosis-activating factor (APAF1) - forms homodimers, & heterodimers with BAX, BAD, BAK & Bcl-X(L) - heterodimerization with BAX requires intact BH1 & BH2 motifs, & is necessary for anti-apoptotic activity - also interacts with APAF1, RAF-1, TP53BP2, BBC3, BCL2L1, MRPL41 & BNIPL - binding to FKBP8 seems to target BCL2 to the mitochondria & probably interferes with binding of BCL2 to its targets - phosphorylation/dephosphorylation on Ser-70 regulates anti- apoptotic activity - growth factor-stimulated phosphorylation on Ser-70 by PKC is required for the anti-apoptosis activity & occurs during the G2/M phase of the cell cycle - in the absence of growth factors, BCL2 appears to be phosphorylated by other protein kinases such as ERKs & stress-activated kinases - dephosphorylated by protein phosphatase 2A (PP2A) (putative) - proteolytically cleaved by caspases during apoptosis - the cleaved protein, lacking the BH4 motif, has pro-apoptotic activity, causes the release of cytochrome c into the cytosol promoting further caspase activity Structure: - BH4 motif is required for anti-apoptotic activity & for interaction with RAF-1 - belongs to the Bcl-2 family Compartment: - mitochondrial outer membrane - nucleus membrane - endoplasmic reticulum membrane Alternative splicing: named isoforms=2; alpha; beta Expression: expressed in a variety of tissues Pathology: - breakpoint translocation t(14,18) [8] involving BCL2 may be a cause of follicular lymphoma - translocation t(14;18)(q32;q21) involving BCL2 with immunoglobulin gene regions are found in non-Hodgkin lymphomas Laboratory: - BCL2 Ag in tissue

Interactions

molecular events

Related

apoptosis Bcl-2 associated protein X (BAX) bcl-2 proto-oncogene cytochrome c (CYCS) PAX5+BCL2 Ag in tissue

Specific

bcl-2 alpha homodimer bcl-2 beta

General

anti apoptotic protein bcl-2 subfamily protein mitochondrial membrane protein nuclear protein oligomerizing protein proto oncogene protein

Properties

SIZE: MW = 26 kD entity length = 239 aa COMPARTMENT: inner mitochondrial membrane nuclear membrane endoplasmic reticulum MOTIF: BH4 domain NAME: BH4 domain SITE: 10-30 proteolytic site {34-35} Ser phosphorylation site {S70} BH3 domain NAME: BH3 domain SITE: 93-107 BH1 domain NAME: BH1 domain SITE: 136-155 BH2 domain NAME: BH2 domain SITE: 187-202 transmembrane domain {212-233}

Database Correlations

OMIM 151430 UniProt P10415 PFAM correlations Entrez Gene 596 KEGG correlations

References

  1. Hockenbery D et al Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334-6. PMID: 2250705
  2. Martin SJ, Green DR, Cotter TG. Dicing with death: dissecting the components of the apoptosis machinery. Trends Biochem Sci. 1994 Jan;19(1):26-30. Review. PMID: 8140617
  3. Yin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 1994 May 26;369(6478):321-3. PMID: 8183370
  4. Lacronique V, Mignon A, Fabre M, Viollet B, Rouquet N, Molina T, Porteu A, Henrion A, Bouscary D, Varlet P, Joulin V, Kahn A. Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med. 1996 Jan;2(1):80-6. PMID: 8564847
  5. Kumar S. ICE-like proteases in apoptosis. Trends Biochem Sci. 1995 May;20(5):198-202. Review. PMID: 7610484
  6. Korsmeyer SJ. Regulators of cell death. Trends Genet. 1995 Mar;11(3):101-5. Review. PMID: 7732571
  7. Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci. 2001 Jan;26(1):61-6. Review. PMID: 11165519
  8. Tsujimoto et al. Science 228:1440-3, 1985
  9. Entrez Gene :accession 596
  10. UniProt :accession P10415
  11. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/BCL2ID49.html
  12. NIEHS-SNPs http://egp.gs.washington.edu/data/bcl2/
  13. Wikipedia; Note: Bcl-2 entry Shttp://en.wikipedia.org/wiki/Bcl-2

Component-of

molecular complex