![Bcl-xl](https://upload.wikimedia.org/wikipedia/commons/a/a9/Bcl-xl.jpg)
B-cell lymphoma-extra large (Bcl-xL), encoded by the
BCL2-like 1 gene, is a transmembrane molecule in the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. It is a member of the
Bcl-2 family
The Bcl-2 familyTC# 1.A.21 consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. ...
of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as
cytochrome c
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
, which leads to
caspase
Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...
activation and ultimately,
programmed cell death
Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage durin ...
.
Function
It is a well-established concept in the field of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
that relative amounts of pro- and anti-survival Bcl-2 family of proteins determine whether the cell will undergo cell death; if more Bcl-xL is present, then pores are non-permeable to pro-apoptotic molecules and the cell survives. However, if
Bax and
Bak become activated, and Bcl-xL is sequestered away by gatekeeper BH3-only factors (e.g.
Bim
''Bim'' is a 1974 Trinidad and Tobago film written by Raoul Pantin and directed by Hugh A. Robertson. It was described by Bruce Paddington as "one of the most important films to be produced in Trinidad and Tobago and... one of the classics of Ca ...
) causing a pore to form, cytochrome c is released leading to initiation of caspase cascade and apoptotic events.
While the exact signaling pathway of Bcl-xL is still not known, it is believed that Bcl-xL differs highly from Bcl-2 in their mechanism of inducing apoptosis. Bcl-xL is about ten times more functional than Bcl-2 when induced by the chemotherapy drug,
Doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used togeth ...
and can specifically bind to cytochrome C residues, preventing apoptosis. It can also prevent the formation of Apaf-1 and Caspase 9 complex by acting directly upon Apaf-1 rather than Caspase 9, as shown in nematode homologs.
Clinical significance
Bcl-xL dysfunction in mice can cause ineffective production of red blood cells, severe anemia, hemolysis, and death. This protein has also been shown as a requirement for heme production and in erythroid lineage, Bcl-xL is a major survival factor responsible for an estimated half of the total survival "signal" proerythroblasts must receive in order to survive and become red cells. Bcl-xL promoter contains
GATA-1 and Stat5 sites. This protein accumulates throughout the differentiation, ensuring the survival of erythroid progenitors. Because iron metabolism and incorporation into hemoglobin occurs inside the mitochondria, Bcl-xL was suggested to play additional roles in regulating this process in erythrocytes which could lead to a role in
polycythemia vera
Polycythemia vera is an uncommon myeloproliferative neoplasm (a type of chronic leukemia) in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets.
Most of the health ...
, a disease where there is an overproduction of erythrocytes.
Similar to other Bcl-2 family members, Bcl-xL has been implicated in the survival of cancer cells by inhibiting the function of
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, a tumor suppressor. In cancerous mouse cells, those which contained Bcl-xL were able to survive while those that only expressed p53 died in a small period of time.
Bcl-xL is a target of various
senolytic
A senolytic (from the words ''senescence'' and ''-lytic'', "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans. A goal of this re ...
agents. Studies of cell cultures of senescent
human umbilical vein endothelial cell
Human umbilical vein endothelial cells (HUVECs) are cells derived from the endothelium of veins from the umbilical cord. They are used as a laboratory model system for the study of the function and pathology of endothelial cells (e.g., angiogenesis ...
s have shown that both
fisetin
Fisetin (7,3′,4′- flavon-3-ol) is a plant flavonol from the flavonoid group of polyphenols. It can be found in many plants, where it serves as a yellow/ochre colouring agent. It is also found in many fruits and vegetables, such as strawberries, ...
and
quercetin
Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor a ...
induce apoptosis by inhibition of Bcl-xL.
Fisetin has roughly twice the senolytic potency as quercetin.
Small molecule Bcl-xL inhibitor that directly binds to Bcl-xL and releases their partner such as Bax, a proapoptotic protein, has been suggested as an anticancer strategy via inducing of apoptosis.
Related proteins
Other Bcl-2 proteins include
Bcl-2
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. ...
,
Bcl-w
Bcl-2-like protein 2 is a 193-amino acid protein that in humans is encoded by the ''BCL2L2'' gene on chromosome 14 (band q11.2-q12). It was originally discovered by Leonie Gibson, Suzanne Cory and colleagues at the Walter and Eliza Hall Institut ...
, Bcl-xs, and
Mcl-1
Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the ''MCL1'' gene.
Function
The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two tr ...
.
References
{{Fas apoptosis signaling pathway
Mitochondria
Cancer research
Apoptosis