Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family
of regulator proteins that regulate cell death, by either inducing it or inhibiting it.
Bcl-2 is specifically considered as an important anti-apoptotic protein and is thus classified
as an oncogene.
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 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 Like BCL3, BCL5, BCL6, BCL7A, BCL9, and BCL10,
it has clinical significance in lymphoma.
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.
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.
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.
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.
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.
Other studies have shown that the lifespan of dendritic cells may be partly controlled
by a timer dependent on anti-apoptotic Bcl-2.
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.
There is some evidence that this defective apoptosis may result from abnormal expression
of Bcl-2 and increased expression of caspase-3.
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.
Targeted therapies Bcl-2 inhibitors include :
Genasense An antisense oligonucleotide drug Genasense
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.
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 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.
These have shown successful results in Phase I/II trials for lymphoma, and a large Phase
III trial was launched in 2004 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 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, which target these
Bcl-2 family proteins, but not A1 or Mcl-1.
ABT-737 is superior to previous BCL-2 inhibitors because this compound has higher affinity
for Bcl-2, Bcl-xL, and Bcl-w.
In in vitro studies, primary cells from patients with B-cell malignancies are extremely sensitive
to ABT-737.
ABT-737 does not directly induce apoptosis; it enhances the effects of the death signals
and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and
lymphoma lines.
In animal models, it improves survival, causes tumor regression, and results in the cure
of a high percentage of mice.
Finally, in preclinical studies utilizing patient xenografts, ABT-737 has shown efficacy
for treating lymphoma and other blood cancers.
ABT-199 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.
Some very good responses have been reported.
Others obatoclax has phase II results for small-cell
lung cancer.
Interactions
Bcl-2 has been shown to interact with:
Human BCL-2 genes BAK; BAK1; BAX; BCL2; BCL2A1; BCL2L1; BCL2L10;
BCL2L13; BCL2L14; BCL2L2; BCL2L7P1; BOK; MCL1; LGALS7
See also
References
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
c-bcl-2 Proteins at the US National Library of Medicine Medical Subject Headings