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the 2nd letter of the Roman alphabet (同)b
the blood group whose red cells carry the B antigen (同)type_B, group B

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/11/07 17:43:47」(JST)

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Bcl-2 (B-cell lymphoma 2), encoded by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis).^[1]^[2]

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. Bcl-2 orthologs^[3] have been identified in numerous mammals for which complete genome data are available. The two isoforms of Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also known as 1G5O/1GJH, exhibit 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]

Role in disease[edit]

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.

Cancer occurs as the result of 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.^[5] In follicular lymphoma, a chromosomal translocation commonly occurs between the fourteenth and the eighteenth chromosomes—t(14;18) — which places the Bcl-2 gene next to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.^[6] This decreases the propensity of these cells for undergoing apoptosis.

Apoptosis also plays a very 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.^[7] 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 most important antigen presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. Researchers have found that mice containing dendritic cells that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal dendritic cells.^[7] Other studies have shown that the lifespan of dendritic cells may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.^[7]

Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. For example, schizophrenia is a neurodegenerative disease that may result from an abnormal ratio of pro- and anti-apoptotic factors.^[8] There is some evidence that this defective apoptosis may result from abnormal expression of Bcl-2 and increased expression of caspase-3.^[8]

Further research into the family of Bcl-2 proteins will provide a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis^{[citation needed]}. An understanding of the mechanisms involved may help develop new therapies for treating cancer, autoimmune conditions, and neurological diseases.

Diagnostic use[edit]

Antibodies to Bcl-2 can be used with immunohistochemistry to identify cells containing the antigen. In healthy tissue, these antibodies will react with B-cells in the mantle zone, as well as some T-cells. However, there is a considerable increase in positive cells 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.^[9]

Targeted therapies[edit]

Bcl-2 inhibitors include :

Genasense[edit]

An antisense oligonucleotide drug Genasense (G3139) has been 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.

It was shown that the proliferation of human lymphoma cells (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.^[10]

These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial was launched in 2004^[11]

By the first quarter 2010, Genasense had not received FDA approval due to disappointing results in a melanoma trial. Although safety and efficacy of Genasense have not been established for any use, Genta Incorporated still claims on its website that studies are currently underway to examine the potential role of Genasense in a variety of clinical indications.

ABT-737[edit]

Abbott Laboratories described in the mid-2000s a novel inhibitor of Bcl-2, Bcl-xL and Bcl-w, known as ABT-737.^[12] ABT-737 is one among many so-called BH3 mimetic small molecule inhibitors (SMI) targeting Bcl-2 and Bcl-2-related proteins such as Bcl-xL and Bcl-w but not A1 and Mcl-1, which may prove valuable in the therapy of lymphoma and other blood cancers.^[13]

ABT-199[edit]

A Phase Ia trial is currently ongoing to study the effects of agent, ABT-199, a so-called BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia.^[14]

January 17, 2013 The study had suspended participant recruitment per a temporary hold ^[15]

Others[edit]

obatoclax (GX15-070) has phase II results for small-cell lung cancer.^[16]

Interactions[edit]

Overview of signal transduction pathways involved in apoptosis.

Bcl-2 has been shown to interact with RAD9A,^[17] BAK1,^[18]^[19] Reticulon 4,^[20] Bcl-2-associated X protein,^[17]^[18]^[21]^[22] Caspase 8,^[23]^[24] BECN1,^[25] SOD1,^[26] Bcl-2-interacting killer,^[27]^[28] BH3 interacting domain death agonist,^[27]^[29] RRAS,^[30] C-Raf,^[31] BCL2L11,^[27]^[32]^[33] BNIPL,^[34]^[35] HRK,^[27]^[36] PSEN1,^[37] BMF,^[38] BNIP2,^[34]^[39] BNIP3,^[39]^[40] Nerve Growth factor IB,^[18] BCL2-like 1,^[18]^[41] Myc,^[42] BCAP31,^[43] SMN1,^[44] CAPN2,^[45] PPP2CA,^[46] Noxa,^[27]^[47] Cdk1,^[48]^[49] TP53BP2,^[50] Bcl-2-associated death promoter^[27]^[51] and IRS1.^[52]

Human BCL-2 genes[edit]

BAK; BAK1; BAX; BCL2; BCL2A1; BCL2L1; BCL2L10; BCL2L13; BCL2L14; BCL2L2; BCL2L7P1; BOK; MCL1; LGALS7 (Galectin-7)

References[edit]

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External links[edit]

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)

UpToDate Contents

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1. 濾胞性リンパ腫の病理生物学 pathobiology of follicular lymphoma
2. びまん性大細胞型B細胞性リンパ腫および原発性縦隔大細胞型B細胞リンパ腫の病理学 pathobiology of diffuse large b cell lymphoma and primary mediastinal large b cell lymphoma
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NAID 40019458199

Mood stabilizers commonly restore staurosporine-induced increase of p53 expression and following decrease of Bcl-2 expression in SH-SY5Y cells

Song Ning,Boku Shuken,Nakagawa Shin,Kato Akiko,Toda Hiroyuki,Takamura Naoki,Omiya Yuki,Kitaichi Yuji,Inoue Takeshi,Koyama Tsukasa
Progress in Neuro-Psychopharmacology and Biological Psychiatry 38(2), 183-189, 2012-08-07
… Past studies have shown that Li and VPA increase the expression of Bcl-2, an anti-apoptotic gene. … In addition, it has been shown that Li decreases the expression of p53, which plays a prominent role in apoptosis and regulates the expression of Bcl-2. … Therefore, p53 and Bcl-2 can be considered to mediate the common anti-apoptotic effects of Li, VPA, CBZ and LTG. …
NAID 120004857013

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★リンクテーブル★

リンク元	「癌遺伝子」「antiapoptotic protein」
拡張検索	「Bcl-2相同拮抗性キラータンパク質」「Bcl-2結合Xタンパク質」「Bcl-2-associated X protein」「c-Bcl-2」「癌原遺伝子産物c-Bcl-2」
関連記事	「bcl-2」「B」

「癌遺伝子」

B-cell CLL/lymphoma 2
	; PDB rendering based on 1GJH,1G5M.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1G5M, 1GJH, 1YSW, 2O21, 2O22, 2O2F, 2W3L, 2XA0, 4AQ3, 4IEH, 4LVT, 4LXD, 4LXE
Identifiers
Symbols	BCL2; Bcl-2; PPP1R50
External IDs	OMIM: 151430 MGI: 88138 HomoloGene: 527 ChEMBL: 4860 GeneCards: BCL2 Gene
Gene Ontology
Molecular function	• protease binding; • protein binding; • transcription factor binding; • channel activity; • ubiquitin protein ligase binding; • identical protein binding; • protein homodimerization activity; • sequence-specific DNA binding; • protein heterodimerization activity; • BH3 domain binding; • protein phosphatase 2A binding;
Cellular component	• nucleus; • cytoplasm; • mitochondrion; • mitochondrial outer membrane; • endoplasmic reticulum; • endoplasmic reticulum membrane; • cytosol; • membrane; • nuclear membrane; • myelin sheath; • pore complex;
Biological process	• G1/S transition of mitotic cell cycle; • protein polyubiquitination; • response to acid; • ossification; • ovarian follicle development; • metanephros development; • branching involved in ureteric bud morphogenesis; • behavioral fear response; • B cell homeostasis; • release of cytochrome c from mitochondria; • regulation of cell-matrix adhesion; • lymphoid progenitor cell differentiation; • B cell lineage commitment; • renal system process; • protein dephosphorylation; • melanin metabolic process; • regulation of nitrogen utilization; • apoptotic process; • humoral immune response; • response to DNA damage stimulus; • actin filament organization; • female pregnancy; • cell aging; • cell death; • male gonad development; • response to radiation; • response to external stimulus; • response to toxic substance; • post-embryonic development; • response to iron ion; • response to UV-B; • response to gamma radiation; • negative regulation of autophagy; • negative regulation of calcium ion transport into cytosol; • regulation of glycoprotein biosynthetic process; • mesenchymal cell development; • positive regulation of neuron maturation; • positive regulation of smooth muscle cell migration; • cell growth; • cell-cell adhesion; • peptidyl-serine phosphorylation; • peptidyl-threonine phosphorylation; • cochlear nucleus development; • gland morphogenesis; • regulation of transmembrane transporter activity; • negative regulation of ossification; • positive regulation of cell growth; • negative regulation of cell growth; • melanocyte differentiation; • negative regulation of cell migration; • positive regulation of B cell proliferation; • hair follicle morphogenesis; • axon regeneration; • regulation of protein stability; • endoplasmic reticulum calcium ion homeostasis; • glomerulus development; • negative regulation of cellular pH reduction; • negative regulation of myeloid cell apoptotic process; • T cell differentiation in thymus; • positive regulation of peptidyl-serine phosphorylation; • negative regulation of osteoblast proliferation; • response to cytokine stimulus; • response to nicotine; • organ growth; • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway; • positive regulation of multicellular organism growth; • B cell proliferation; • response to drug; • response to hydrogen peroxide; • T cell homeostasis; • negative regulation of apoptotic process; • positive regulation of catalytic activity; • CD8-positive, alpha-beta T cell lineage commitment; • regulation of protein homodimerization activity; • regulation of protein heterodimerization activity; • negative regulation of neuron apoptotic process; • ear development; • regulation of viral genome replication; • innate immune response; • positive regulation of melanocyte differentiation; • negative regulation of mitotic cell cycle; • negative regulation of retinal cell programmed cell death; • regulation of mitochondrial membrane permeability; • focal adhesion assembly; • spleen development; • thymus development; • digestive tract morphogenesis; • developmental growth; • oocyte development; • positive regulation of skeletal muscle fiber development; • pigment granule organization; • homeostasis of number of cells within a tissue; • B cell receptor signaling pathway; • response to glucocorticoid stimulus; • neuron apoptotic process; • defense response to virus; • regulation of mitochondrial membrane potential; • negative regulation of mitochondrial depolarization; • regulation of calcium ion transport; • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; • cellular response to organic substance; • reactive oxygen species metabolic process; • intrinsic apoptotic signaling pathway; • positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; • negative regulation of anoikis; • negative regulation of apoptotic signaling pathway; • positive regulation of intrinsic apoptotic signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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