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before the Christian era; used following dates before the supposed year Christ was born; "in 200 BC" (同)B.C., before Christ

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2021/06/29 17:37:01」(JST)

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Bcl-2（B-cell lymphoma 2）はヒトではBCL2遺伝子にコードされるタンパク質で、細胞死（アポトーシス）の阻害または誘導のいずれかを行うBcl-2ファミリー（英語版）の最初に発見されたメンバーである^[5]^[6]。

Bcl-2の名称はB-cell lymphoma 2に由来し、濾胞性リンパ腫における14番染色体と18番染色体間の染色体転座に関与するタンパク質として2番目に記載されたメンバーであることを意味している。BCL2のオルソログ^[7]（マウスのBcl2など）は、全ゲノムデータが利用可能な哺乳類の多数で同定されている。

BCL3（英語版）、BCL5、BCL6（英語版）、BCL7A、BCL9（英語版）、BCL10（英語版）と同様、リンパ腫において臨床的に重要である。

アイソフォーム

Bcl-2には2つのアイソフォーム（アイソフォーム1、2）が存在し、両者のフォールディングは同じである。しかし、これら2つのアイソフォームはBAD（英語版）やBAK（英語版）タンパク質に対する結合能や、構造的トポロジー、結合が行われる溝の静電ポテンシャルが異なり、両者の抗アポトーシス活性には差異が存在することが示唆される^[8]。

正常な生理学的機能

Bcl-2はミトコンドリアの外膜に局在しており、そこで細胞の生存の促進とアポトーシス促進タンパク質の作用の阻害に重要な役割を果たす。通常、BaxやBakを含むBcl-2ファミリーのアポトーシス促進タンパク質は、ミトコンドリア膜に作用し、膜の透過性を高め、アポトーシスカスケードの重要シグナルとなるシトクロムcや活性酸素種の放出を促進する。これらのアポトーシス促進タンパク質はBH3-onlyタンパク質によって活性化され、Bcl-2と関連タンパク質Bcl-xL（英語版）の機能によって阻害される^[9]。

さらに、Bcl-2の非典型的役割についても研究が行われている。Bcl-2はミトコンドリアのダイナミクスを調節することが知られており、ミトコンドリアの融合と分裂の調節に関与している。さらに膵臓のβ細胞では、Bcl-2とBcl-xLは代謝活性とインスリン分泌の制御に関与していることが知られており、Bcl-2/xLの阻害によって代謝活性が増加するが、活性酸素種の産生もさらに増加する。このことからは、Bcl-2/xLは代謝要求が高い条件下で代謝を保護する効果があることが示唆される^[10]。

疾患における役割

「en:Apoptosis#Implication in disease」も参照

Bcl-2の遺伝子の損傷は、悪性黒色腫、乳がん、前立腺がん、慢性リンパ性白血病、肺がんを含む多数のがんの原因として同定されており、統合失調症や自己免疫疾患の原因となっている可能性もある。がん治療に対する抵抗性の原因でもある^[11]。

がん

がんは、細胞成長と細胞死の間の恒常性の障害としてとらえることができる。抗アポトーシス遺伝子の過剰発現やアポトーシス促進遺伝子の発現低下によって、がんの特徴である細胞死の欠如がもたらされる。リンパ腫を例に挙げると、抗アポトーシスタンパク質Bcl-2のリンパ球での過剰発現だけではがんは引き起こされない。しかし、Bcl-2のとがん原遺伝子であるmycの過剰発現が同時に起こると、リンパ腫を含むアグレッシブB細胞悪性腫瘍が生じる可能性がある^[12]。濾胞性リンパ腫では14番染色体と18番染色体間の染色体転座（t(14;18)）が一般的に生じており、それによって18番染色体のBcl-2の遺伝子は14番染色体の免疫グロブリン重鎖の遺伝子座に隣接して置かれることとなる。この融合遺伝子は調節を受けず、Bcl-2が過剰に高いレベルで転写される^[13]。これによって細胞のアポトーシス傾向が低下する。Bcl-2の発現は小細胞肺がん（英語版）でも頻繁に生じており、ある研究では症例の76%にのぼる^[14]。

自己免疫疾患

アポトーシスは免疫系の調節に活発な役割を果たしている。アポトーシスが正常に機能しているときには、中枢性と末梢性の免疫寛容によって自己抗原に対しては免疫無応答となる。アポトーシスに欠陥がある場合、自己免疫疾患の病態に寄与する可能性がある^[15]。自己免疫疾患である1型糖尿病では、T細胞の活性化誘導細胞死（英語版）（AICD）の異常と末梢性免疫寛容の欠陥が引き起こされる。免疫系で最も重要な抗原提示細胞は樹状細胞であるため、その活性はアポトーシスなどの機構によって厳密に調節されなければならない。樹状細胞の寿命は抗アポトーシスタンパク質であるBcl-2に依存したタイマーによって部分的に制御されていることが示されている^[16]。

その他

アポトーシスはさまざまな疾患の調節に重要な役割を果たす。例えば統合失調症は、アポトーシス促進タンパク質と抑制タンパク質の比率の異常が病因に関係している可能性がある^[17]。一部のエビデンスは、それがBcl-2の異常発現とカスパーゼ3の発現上昇によるものである可能性を示唆している^[17]。

診断における利用

Bcl-2に対する抗体は、免疫染色による抗原を含む細胞の同定に利用される。健康な組織では、これらの抗体はmantle zone（マントル層、帽状域）のB細胞や一部のT細胞と反応する。しかし、濾胞性リンパ腫や他のがんでは陽性細胞が大きく増加する。生検時のBcl-2染色の有無は、患者の予後や再発可能性の判断に重要となる場合もある^[18]。

標的治療

Bcl-2を標的とした選択的阻害剤が開発されており、現在臨床利用が行われている。

オブリメルセン

オブリメルセン（英語版）（G3139）は、Genta社によって開発されたBcl-2を標的としたアンチセンス医薬品（アンチセンスオリゴヌクレオチド）である。DNAまたはRNAのアンチセンス鎖は、コーディング鎖（RNAやタンパク質の産生の鋳型となる鎖）に対して相補的な鎖である。アンチセンス医薬品はmRNAとハイブリダイゼーションを行う短いRNA配列で、mRNAを不活性化してタンパク質の産生を防ぐ。

ヒトのリンパ腫細胞のt(14;18)転座による増殖は、Bcl-2のmRNAの開始コドン領域を標的としたアンチセンスRNAによって阻害される。In vitroでの研究によって、Bcl-2のmRNAの最初の6つのコドンに対して相補的なオブリメルセンが同定された^[19]。リンパ腫に対する第I/II相試験で良好な結果を残し、大規模第III相試験が2004年に開始された。2016年の段階で薬剤は承認されておらず、開発元は廃業している^[20]。

ABT-737とナビトクラックス（ABT-263）

2000年代半ばに、アボット・ラボラトリーズはABT-737（英語版）と呼ばれるBcl-2、Bcl-xL、Bcl-wに対する新規阻害薬を開発した。この化合物はBH3を模倣した低分子阻害薬で、これらのBcl-2ファミリータンパク質を標的とするが、A1やMcl-1は標的とはならない。ABT-737はBcl-2、Bcl-xL、Bcl-wに対してより高い親和性で結合する点でこれまでのBcl-2阻害剤よりも優れていた。In vitroでの研究によって、B細胞悪性腫瘍の患者由来の初代細胞はABT-737に対する感受性を示した^[21]。

動物モデルでは、ABT-737は生存率を改善し、腫瘍の退縮を引き起こし、高い割合でマウスを治癒した^[22]。患者由来の異種移植片を用いた臨床前研究では、ABT-737はリンパ腫や他の血液のがんの治療に効力を示した^[23]。ABT-737の薬理学的性質は臨床試験に適していなかったが、経口バイオアベイラビリティの高い誘導体ナビトクラックス（英語版）（ABT-263）は小細胞肺がん細胞株に対して同様の活性を示し、臨床試験が開始された^[24]。ナビトクラックスに対する臨床反応は有望なものであったが、血小板でのBcl-xLの阻害のため、血小板減少症（英語版）による用量制限毒性が治療中の患者で見られた^[25]^[26]^[27]。

ベネトクラクス（ABT-199）

ナビトクラックスのBcl-xLの阻害による血小板減少症のため、アッヴィは選択性がきわめて高い阻害薬ベネトクラクス（ABT-199）の開発を行った。ベネトクラクスはBcl-2を阻害するが、Bcl-xLやBcl-wは阻害しない^[28]。慢性リンパ性白血病（CLL）の患者に対して、Bcl-2タンパク質の機能を遮断するようデザインされたBH3模倣薬であるベネトクラクスの効果を研究する臨床試験が行われた^[29]^[30]。良好な反応が報告され、血小板減少症はみられなかった^[30]^[31]。第III相試験は2015年12月に開始された^[32]。2016年4月、染色体の17pの欠失と関係したCLLに対する第二選択薬としてアメリカ食品医薬品局（FDA）によって承認された^[33]。これは、Bcl-2阻害薬としてFDAに承認された最初の薬剤である^[33]。2018年6月FDAは、第二選択薬としてではあるが、17p欠失の有無に関係なく、すべてのCLLと小リンパ球性リンパ腫へと承認を拡大した^[34]。

相互作用

アポトーシスに関与するシグナル伝達経路の概要

Bcl-2は次に挙げる因子と相互作用することが示されている。

BAK1（英語版）^[35]^[36]
BCAP31（英語版）^[37]
BCL2L1（英語版）^[35]^[38]
BCL2L11（英語版）^[39]^[40]^[41]
BECN1（英語版）^[42]
BID（英語版）^[39]^[43]
BMF（英語版）^[44]
BNIP2（英語版）^[45]^[46]
BNIP3（英語版）^[46]^[47]
BNIPL（英語版）^[45]^[48]
BAD（英語版）^[39]^[49]
BAX^[35]^[50]^[51]^[52]
BIK（英語版）^[39]^[53]
RAF1^[54]
CAPN2（英語版）^[55]
CASP8^[56]^[57]
CDK1^[58]^[59]
HRK（英語版）^[39]^[60]
IRS1^[61]
Myc^[62]
NR4A1（英語版）^[35]
PMAIP1（英語版）^[39]^[63]
PPP2CA（英語版）^[64]
PSEN1（英語版）^[65]
RAD9A（英語版）^[50]
RRAS（英語版）^[66]
RTN4（英語版）^[67]
SMN1（英語版）^[68]
SOD1（英語版）^[69]
TP53BP2（英語版）^[70]

出典

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外部リンク

The Bcl-2 Family Database
The Bcl-2 Family at celldeath.de
Bcl-2 publications sorted by impact at caspases.org
bcl-2 Genes - MeSH・アメリカ国立医学図書館・生命科学用語シソーラス（英語）
c-bcl-2 Proteins - MeSH・アメリカ国立医学図書館・生命科学用語シソーラス（英語）
Human BCL2 genome location and BCL2 gene details page in the UCSC Genome Browser.

wiki en

[Wiki en表示]

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] It was the first apoptosis regulator identified in any organism.^[7]

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^[8] (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, and Isoform 2, 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.^[9]

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.^[10]

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,^[11] but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.^[12]

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.^[13]

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.^[14] 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.^[15] This decreases the propensity of these cells for apoptosis. Bcl-2 expression is frequent in small cell lung cancer, accounting for 76% cases in one study.^[16]

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.^[17] 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.^[17] Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.^[17]

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.^[18] Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of caspase-3.^[18]

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.^[19]

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.^[20]

These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.^[21] As of 2016, the drug had not been approved and its developer was out of business.^[22]

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.^[23] 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.^[24] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.^[25] 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.^[26] While clinical responses with navitoclax were promising, mechanistic dose-limiting thrombocytopoenia was observed in patients under treatment due to Bcl-xL inhibition in platelets.^[27]^[28]^[29]

Venetoclax (ABT-199)

Due to dose-limiting thrombocytopenia 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.^[30] 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).^[31]^[32] Good responses have been reported and thrombocytopoenia was no longer observed.^[32]^[33] A phase 3 trial started in Dec 2015.^[34] It was approved by the US FDA in April 2016 as a second-line treatment for CLL associated with 17-p deletion.^[35] This was the first FDA approval of a BCL-2 inhibitor.^[35] 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.^[36]

Interactions

Overview of signal transduction pathways involved in apoptosis.

Bcl-2 has been shown to interact with:

BAK1,^[37]^[38]
BCAP31,^[39]
BCL2-like 1,^[37]^[40]
BCL2L11,^[41]^[42]^[43]
BECN1,^[44]
BID,^[41]^[45]
BMF,^[46]
BNIP2,^[47]^[48]
BNIP3,^[48]^[49]
BNIPL,^[47]^[50]
BAD^[41]^[51]
BAX,^[37]^[52]^[53]^[54]
BIK,^[41]^[55]
C-Raf,^[56]
CAPN2,^[57]
CASP8,^[58]^[59]
Cdk1,^[60]^[61]
HRK,^[41]^[62]
IRS1,^[63]
Myc,^[64]
NR4A1,^[37]
Noxa,^[41]^[65]
PPP2CA,^[66]
PSEN1,^[67]
RAD9A,^[52]
RRAS,^[68]
RTN4,^[69]
SMN1,^[70]
SOD1,^[71] and
TP53BP2.^[72]

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^ ^a ^b Boyd 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. S2CID 38609845.
^ 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. S2CID 10343291.
^ ^a ^b Komatsu 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. S2CID 52847351.
^ 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. S2CID 31151334.
^ 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. S2CID 16559750.
^ 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. S2CID 4312803.
^ 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. S2CID 1936633.
^ 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. S2CID 18141051.
^ 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.
Overview of all the structural information available in the PDB for UniProt: P10415 (Human Apoptosis regulator Bcl-2) at the PDBe-KB.

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.

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
3. 慢性リンパ性白血病の病態生理および遺伝学的特徴 pathophysiology and genetic features of chronic lymphocytic leukemia
4. 濾胞性リンパ腫の臨床症状、病理学的特徴、診断、および予後 clinical manifestations pathologic features diagnosis and prognosis of follicular lymphoma
5. バーキットリンパ腫の疫学、臨床症状、病理学的特徴、および診断 epidemiology clinical manifestations pathologic features and diagnosis of burkitt lymphoma

English Journal

BAFF maintains T-cell survival by inducing OPN expression in B cells.

Ma N, He Y, Xiao H, Han G, Chen G, Wang Y, Wang K, Hou C, Yang X, Marrero B, Wang Y, Shen B, Li Y, Wang R.SourceLaboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, China; Department of Rheumatology, First Hospital of Jilin University, Changchun 130021, China.
Molecular immunology.Mol Immunol.2014 Feb;57(2):129-37. doi: 10.1016/j.molimm.2013.08.014. Epub 2013 Sep 28.
Dysregulation of T-cell survival and apoptosis is the common cause of autoimmune diseases such as multiple sclerosis (MS). However, the factors inducing imbalance of T-cell survival and apoptosis in MS remains unclear. Here, we show that the resistance to apoptosis was associated with high levels of
PMID 24084099

Screening for possible miRNA-mRNA associations in a colon cancer cell line.

Kanematsu S, Tanimoto K, Suzuki Y, Sugano S.SourceGraduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.
Gene.Gene.2014 Jan 10;533(2):520-31. doi: 10.1016/j.gene.2013.08.005. Epub 2013 Aug 9.
MicroRNAs (miRNAs) are small non-coding RNAs mediating the regulation of gene expression in various biological contexts, including carcinogenesis. Here, we screened putative associations between 34, 45, and 103 miRNAs and 164, 391, and 81 mRNAs via Argonaute1 (Ago1) or Ago2 immunoprecipitation (IP)
PMID 23939471

Japanese Journal

The Association between Smoking and Ectopic Pregnancy: Why Nicotine Is BAD for Your Fallopian Tube

Horne Andrew W.,Brown Jeremy K.,Nio-Kobayashi Junko,Abidin Hazirah B. Z.,Adin Zety E. H. A.,Boswell Lyndsey,Burgess Stewart,Lee Kai-Fai,Duncan W. Colin
Plos One 9(2), e89400, 2014-02-20
… Consistent with the array data, smoking was associated with decreased levels of BAD transcript (P<0.01) and increased levels of BCL2 transcript (P<0.05) in Fallopian tube biopsies. … BAD and BCL2 specific immunolabelling was localized to Fallopian tube epithelium. …
NAID 120005427748

印環細胞様を呈した濾胞性リンパ腫の 1 例

丸喜明,有田茂実,酒井えり,中山茂,平田哲士,杉山孝弘,伊丹真紀子,堀江弘
日本臨床細胞学会雑誌 53(3), 213-217, 2014
… 異型細胞は, 免疫組織化学染色にて CD10, CD20, BCL2 が陽性であった.結論 : 本例は, 顎下リンパ節では印環細胞様を呈していなかったが, 気管分岐下リンパ節では印環細胞様を呈した濾胞性リンパ腫であった. …
NAID 130004513257

Rheumatoid Arthritis/Methotrexate-associated Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type

Matsumoto Yosuke,Horiike Shigeo,Maekawa Saori,Isohisa Taro,Sakamoto Natsumi,Chinen Yoshiaki,Nakayama Ryuko,Kiyota Miki,Nagoshi Hisao,Mizutani Shinsuke,Shimura Yuji,Sugitani Mio,Kobayashi Tsutomu,Nakai Noriaki,Kuroda Junya,Taniwaki Masafumi
Internal Medicine 53(11), 1177-1181, 2014
… A histological analysis showed diffuse proliferation of large neoplastic B-cells that were immunophenotypically CD10-/MUM1+/BCL6-/BCL2+ and cytogenetically had IgH/c-MYC translocation without translocation involving BCL6 or IgH/BCL2. …
NAID 130004466331

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★リンクテーブル★

リンク元	「18番染色体」「14番染色体」「t(14;18)」
関連記事	「BC」

「18番染色体」

BCL2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1G5M, 1GJH, 1YSW, 2O21, 2O22, 2O2F, 2W3L, 2XA0, 4AQ3, 4IEH, 4LVT, 4LXD, 4MAN, 5AGW, 5AGX, 5FCG
Identifiers
Aliases	BCL2, Bcl-2, PPP1R50, B-cell CLL/lymphoma 2, apoptosis regulator, BCL2 apoptosis regulator
External IDs	OMIM: 151430 MGI: 88138 HomoloGene: 527 GeneCards: BCL2
Gene location (Human)
Chr.	Chromosome 18 (human)
End	63,320,128 bp
Gene location (Mouse)
Chr.	Chromosome 1 (mouse)
End	106,714,274 bp
RNA expression pattern
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	• protein phosphatase binding; • transcription factor binding; • protein phosphatase 2A binding; • channel inhibitor activity; • protein homodimerization activity; • channel activity; • protease binding; • GO:0001948 protein binding; • sequence-specific DNA binding; • BH3 domain binding; • identical protein binding; • protein heterodimerization activity; • ubiquitin protein ligase binding;
Cellular component	• cytoplasm; • cytosol; • nuclear membrane; • membrane; • mitochondrion; • nucleus; • mitochondrial membrane; • myelin sheath; • mitochondrial outer membrane; • endoplasmic reticulum; • pore complex; • integral component of membrane; • intracellular anatomical structure; • endoplasmic reticulum membrane; • nucleoplasm; • protein-containing complex;
Biological process	• 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; • GO:0048554 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 population 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 population 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; • GO:0048552 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 population 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; • hemopoiesis; • regulation of growth; • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator;
	Sources:Amigo / QuickGO
Orthologs
	596
	12043
	ENSG00000171791
	ENSMUSG00000057329
	P10415
	P10417
	NM_000633; NM_000657
	NM_009741; NM_177410
	NP_000624; NP_000648
	NP_033871; NP_803129
	Wikidata
View/Edit Human	View/Edit Mouse

BCL2
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	1G5M, 1GJH, 1YSW, 2O21, 2O22, 2O2F, 2W3L, 2XA0, 4AQ3, 4IEH, 4LVT, 4LXD, 4MAN, 5AGW, 5AGX, 5FCG
識別子
記号	BCL2, Bcl-2, PPP1R50, B-cell CLL/lymphoma 2, apoptosis regulator, BCL2 apoptosis regulator
外部ID	OMIM: 151430 MGI: 88138 HomoloGene: 527 GeneCards: BCL2
遺伝子の位置 (ヒト)
染色体	18番染色体 (ヒト)
終点	63,320,128 bp
遺伝子の位置 (マウス)
染色体	1番染色体 (マウス)
終点	106,714,274 bp
RNA発現パターン
	; ; ; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• protein phosphatase binding; • 転写因子結合; • protein phosphatase 2A binding; • channel inhibitor activity; • protein homodimerization activity; • チャネル活性; • protease binding; • 血漿タンパク結合; • sequence-specific DNA binding; • BH3 domain binding; • identical protein binding; • protein heterodimerization activity; • ubiquitin protein ligase binding;
細胞の構成要素	• 細胞質; • 細胞質基質; • 核膜; • 膜; • ミトコンドリア; • 細胞核; • ミトコンドリア膜; • myelin sheath; • ミトコンドリア外膜; • 小胞体; • pore complex; • integral component of membrane; • 細胞内; • endoplasmic reticulum membrane; • 核質; • 高分子複合体;
生物学的プロセス	• 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; • ステロイドホルモンへの反応; • positive regulation of catalytic activity; • ear development; • 糸球体発生; • 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; • 発生中の色素沈着; • hair follicle morphogenesis; • B cell differentiation; • 細胞増殖; • 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 population 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; • 骨形成; • positive regulation of melanocyte differentiation; • axon regeneration; • 腎臓発生; • actin filament organization; • 胸腺発生; • negative regulation of intrinsic apoptotic signaling pathway; • negative regulation of apoptotic signaling pathway; • response to nicotine; • 脾臓発生; • endoplasmic reticulum calcium ion homeostasis; • positive regulation of skeletal muscle fiber development; • 酸化ストレスへの反応; • 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; • 毒性物質への反応; • digestive tract morphogenesis; • neuron apoptotic process; • 男性生殖腺発生; • 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; • 卵胞発生; • 遺伝子発現調節; • negative regulation of calcium ion transport into cytosol; • negative regulation of osteoblast proliferation; • homeostasis of number of cells within a tissue; • 色素沈着; • 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; • 糖質コルチコイドへの反応; • 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; • 免疫系発生; • apoptotic mitochondrial changes; • peptidyl-serine phosphorylation; • 窒素利用の制御; • cell morphogenesis; • positive regulation of cell population 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; • 薬物への反応; • release of cytochrome c from mitochondria; • negative regulation of mitotic cell cycle; • extrinsic apoptotic signaling pathway in absence of ligand; • アポトーシス; • 膜貫通輸送; • intrinsic apoptotic signaling pathway in response to DNA damage; • 成長; • cell-cell adhesion; • サイトカイン媒介シグナル伝達経路; • negative regulation of apoptotic process; • 造血; • regulation of growth; • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator;
	出典:Amigo / QuickGO
オルソログ
	596
	12043
	ENSG00000171791
	ENSMUSG00000057329
	P10415
	P10417
	NM_000633; NM_000657
	NM_009741; NM_177410
	NP_000624; NP_000648
	NP_033871; NP_803129
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

　　[★]

英: chromosome 18
同: 第18番染色体、第18染色体

t(11;18)(q21;21)：API2-MALT1：H.pylori除菌が無効な胃MALTリンパ腫
t(14;18)［IGH /BCL2］濾胞リンパ腫

「14番染色体」

　　[★]

英: chromosome 14
同: 第14番染色体、第14染色体

t(8;14)(q24;q32)［MYC /IgH］バーキットリンパ腫
t(14;18)［IGH /BCL2］濾胞リンパ腫

「t(14;18)」

　　[★]

t(14;18)［IGH /BCL2］濾胞リンパ腫

「BC」

　　[★] バシトラシン bacitracin

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000171791 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000057329 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

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[7] “ENSG00000171791_BCL2”. www.orthomam.univ-montp2.fr. 2020年5月14日閲覧。

[Human_Bcl2_1G5M-8] PDB 1G5M; “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. (March 2001). Bibcode: 2001PNAS...98.3012P. doi:10.1073/pnas.041619798. PMC: 30598. PMID 11248023.

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[:2-10] “Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ß-Cells”. Endocrinology 157 (6): 2270–2281. (2016). doi:10.1210/en.2015-1964. PMID 27070098.

[pmid30544835-11] “Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy”. International Journal of Molecular Sciences 19 (12): 3950. (Dec 2018). doi:10.3390/ijms19123950. PMC: 6321604. PMID 30544835.

[pmid17179226-12] “Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA”. Blood 109 (7): 3069–75. (Apr 2007). doi:10.1182/blood-2006-08-043257. PMC: 1852223. PMID 17179226.

[pmid3262202-13] “Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells”. Nature 335 (6189): 440–2. (Sep 1988). Bibcode: 1988Natur.335..440V. doi:10.1038/335440a0. PMID 3262202.

[14] Kaiser, U.; Schilli, M.; Haag, U.; Neumann, K.; Kreipe, H.; Kogan, E.; Havemann, K. (1996-08). “Expression of bcl-2--protein in small cell lung cancer”. Lung Cancer (Amsterdam, Netherlands) 15 (1): 31–40. doi:10.1016/0169-5002(96)00568-5. ISSN 0169-5002. PMID 8865121.

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[pmid12445555-19] “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. (Nov 2002). doi:10.1016/S0939-6411(02)00060-7. PMID 12445555.

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[24] Hauck, Paula; Chao, Bo H.; Litz, Julie; Krystal, Geoffrey W. (2009-04). “Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737”. Molecular Cancer Therapeutics 8 (4): 883–892. doi:10.1158/1535-7163.MCT-08-1118. ISSN 1535-7163. PMID 19372561.

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[:10-29] Liao, Grace (2011年8月12日). “ABT-199 BH-3 Mimetic Enters Phase Ia Trial For Chronic Lymphocytic Leukemia”. Asian Scientist 2016年2月11日閲覧。

[:0-30] “Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia”. The New England Journal of Medicine 374 (4): 311–22. (January 2016). doi:10.1056/NEJMoa1513257. PMID 26639348.

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[ASH2015-V-32] Smith, Michael (2015年12月7日). “Hard-to-Treat CLL Yields to Investigational Drug”. 2020年5月4日閲覧。

[Bankhead2016-33] Bankhead, Charles (2016年4月11日). “FDA Approves AbbVie's BCL-2 Targeting Drug for CLL” (英語). Medpage Today

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[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000057329 - Ensembl, May 2017

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[Human_Bcl2_1G5M-9] 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. Bibcode:2001PNAS...98.3012P. doi:10.1073/pnas.041619798. PMC 30598. PMID 11248023.

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[12] 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.

[pmid30544835-13] Garcia-Aranda M, Perez-Ruiz E, Redondo M (December 2018). "Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy". International Journal of Molecular Sciences. 19 (12): 3950. doi:10.3390/ijms19123950. PMC 6321604. PMID 30544835.

[pmid17179226-14] 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.

[pmid3262202-15] 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. S2CID 23593952.

[16] Kaiser, U.; Schilli, M.; Haag, U.; Neumann, K.; Kreipe, H.; Kogan, E.; Havemann, K. (August 1996). "Expression of bcl-2 — protein in small cell lung cancer". Lung Cancer. 15 (1): 31–40. doi:10.1016/0169-5002(96)00568-5. PMID 8865121.

[pmid17162368-17] Li 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.

[pmid16226876-18] Glantz 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. S2CID 22388783.

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[pmid12445555-20] 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.

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[22] "Genasense (oblimersen sodium) FDA Approval Status - Drugs.com". www.drugs.com. Retrieved 11 February 2016.

[23] Vogler, M.; Dinsdale, D.; Dyer, M. J. S.; Cohen, G. M. (March 2009). "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy". Cell Death & Differentiation. 16 (3): 360–367. doi:10.1038/cdd.2008.137. PMID 18806758. S2CID 24538054.

[24] 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. S2CID 4335635.

[25] 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.

[hauck2009-26] Hauck, P.; Chao, B. H.; Litz, J.; Krystal, G. W. (1 April 2009). "Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737". Molecular Cancer Therapeutics. 8 (4): 883–892. doi:10.1158/1535-7163.MCT-08-1118. PMID 19372561. S2CID 19245418.

[27] 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.

[28] 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.

[29] 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. S2CID 10685695.

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BCL2