Bcl-2

B-cell CLL/lymphoma 2

PDB rendering based on 1GJH,1G5M.
Identifiers
Symbols BCL2; Bcl-2
External IDs OMIM: 151430 MGI: 88138 HomoloGene: 527 GeneCards: BCL2 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 596 12043
Ensembl ENSG00000171791 ENSMUSG00000057329
UniProt P10415 Q4VBF6
RefSeq (mRNA) NM_000633.2 NM_009741
RefSeq (protein) NP_000624.2 NP_033871
Location (UCSC) Chr 18:
60.79 – 60.99 Mb		 Chr 1:
108.43 – 108.61 Mb
PubMed search [1] [2]

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

Contents

Role in disease

The Bcl-2 gene has been implicated in a number of cancers, including melanoma, breast, prostate, and lung carcinomas, as well as schizophrenia and autoimmunity. It is also thought to be involved in resistance to conventional cancer treatment. This suggests that decreased apoptosis may play a role in the development of cancer.

Cancer occurs when the homeostatic balance between cell growth and cell death is disturbed. Research in cancer biology has discovered that a variety of aberrations in gene expression of anti-apoptotic, pro-apoptotic and BH3-only proteins can contribute to the many forms of the disease. 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. An understanding of the mechanisms involved may help develop new therapies for treating cancer, autoimmune conditions, and neurological diseases.

Diagnostic use

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

Bcl-2 inhibitors include :

Genasense

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

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]

Others

Interactions

Bcl-2 has been shown to interact with RAD9A,[15] BAK1,[16][17] Reticulon 4,[18] Bcl-2-associated X protein,[15][16][19][20] Caspase 8,[21][22] BECN1,[23] SOD1,[24] Bcl-2-interacting killer,[25][26] BH3 interacting domain death agonist,[25][27] RRAS,[28] C-Raf,[29] BCL2L11,[25][30][31] BNIPL,[32][33] HRK,[25][34] PSEN1,[35] BMF,[36] BNIP2,[32][37] BNIP3,[37][38] Nerve Growth factor IB,[16] BCL2-like 1,[16][39] Myc,[40] BCAP31,[41] SMN1,[42] CAPN2,[43] PPP2CA,[44] Noxa,[25][45] Cdk1,[46][47] TP53BP2,[48] Bcl-2-associated death promoter[25][49] and IRS1.[50]

Human BCL-2 genes

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

See also

References

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External links

Ligand
ONCO: c-Sis/PDGF · HGF
Receptor
TSP: CDH1
TSP: PTCH1
ONCO: c-Kit - Flt3
Intracellular signaling P+Ps
ONCO: Beta-catenin · TSP: APC
TSP: SMAD2, SMAD4
TSP: PTEN · ONCO: c-Akt
Other/unknown
TSP: Maspin · ONCO: c-Src
Nucleus
TSP: p53 · pRb · WT1 · p16/p14arf · ONCO: CDK4 · Cyclin D · Cyclin E
ONCO: BRCA1 - BRCA2
TSP: VHL  · ONCO: CBL - MDM2
TSP: KLF6  · ONCO: AP-1 (c-Fos, c-Jun) - c-Myc
Mitochondria
Other/ungrouped
c-Bcl-2 - Notch - Stathmin

M: NEO

tsoc, mrkr

tumr, epon, para

drug (L1i/1e/V03)
Fas path
TNF path

TRADD

FADD · Caspase 8 · Caspase 3 · BID

TRAF2 · ASK-1 · MEKK1 · IKK · IκBα · MKK7 · JNK · NF-κB
Other
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)