Bcl-2

Source: Wikipedia, the free encyclopedia.

BCL2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000171791

ENSMUSG00000057329

UniProt

P10415

P10417

RefSeq (mRNA)

NM_000633
NM_000657

NM_009741
NM_177410

RefSeq (protein)

NP_000624
NP_000648

NP_033871
NP_803129

Location (UCSC)Chr 18: 63.12 – 63.32 MbChr 1: 106.47 – 106.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2

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

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

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

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

See also: Apoptosis implication 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

small cell lung cancer, accounting for 76% cases in one study.[16]

Auto-immune diseases

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, have 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

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

antisense drug is a short sequence of RNA that hybridises with and inactivates mRNA, preventing the protein
from being formed.

Human

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.

small cell lung cancer (SCLC) cell lines and has entered clinical trials.[26] While clinical responses with navitoclax were promising, mechanistic dose-limiting thrombocytopenia 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 thrombocytopenia 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:

See also

  • Senolytics

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000171791 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000057329 – Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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External links
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