Bcl-xL: Difference between revisions
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[[File:Bcl-xl.jpg|thumb|X-ray crystal structure of Bcl-xL with 1.76 Å resolution]] |
[[File:Bcl-xl.jpg|thumb|X-ray crystal structure of Bcl-xL with 1.76 Å resolution]] |
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'''B-cell lymphoma-extra large''' ('''Bcl- |
'''B-cell lymphoma-extra large''' ('''Bcl-xL'''), encoded by the [[BCL2-like 1 (gene)|BCL2-like 1 gene]], is a transmembrane molecule in the [[mitochondria]]. It is a member of the [[Bcl-2 family]] of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as [[cytochrome c]], which leads to [[caspase]] activation and ultimately, [[Apoptosis|programmed cell death]].<ref>{{cite journal|last1=Korsmeyer|first1=Stanley J.|title=Regulators of Cell Death|journal=Trends in Genetics|date=March 1995|volume=11|issue=3|pages=101–105|doi=10.1016/S0168-9525(00)89010-1|url=http://www.sciencedirect.com/science/article/pii/S0168952500890101|accessdate=5 November 2016}}</ref> |
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==Function== |
==Function== |
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It is a well-established concept in the field of [[apoptosis]] 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 [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|Bak]] become activated, and Bcl-xL is sequestered away by gatekeeper BH3-only factors (e.g. [[BCL2L11|Bim]]), causing a pore to form, cytochrome c is released leading to initiation of caspase cascade leading to apoptotic events.<ref>{{cite journal|last1=Finucane|first1=Deborah M.|last2=Et al|title=Bax-induced Caspase Activation and Apoptosis via Cytochromec Release from Mitochondria Is Inhibitable by Bcl-xL|journal=The Journal of Biological Chemistry|date=January 22, 1999|volume=274|pages=2225–2233|doi=10.1074/jbc.274.4.2225|url=http://www.jbc.org/content/274/4/2225.full}}</ref> |
It is a well-established concept in the field of [[apoptosis]] 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 [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|Bak]] become activated, and Bcl-xL is sequestered away by gatekeeper BH3-only factors (e.g. [[BCL2L11|Bim]]), causing a pore to form, cytochrome c is released leading to initiation of caspase cascade leading to apoptotic events.<ref>{{cite journal|last1=Finucane|first1=Deborah M.|last2=Et al|title=Bax-induced Caspase Activation and Apoptosis via Cytochromec Release from Mitochondria Is Inhibitable by Bcl-xL|journal=The Journal of Biological Chemistry|date=January 22, 1999|volume=274|pages=2225–2233|doi=10.1074/jbc.274.4.2225|url=http://www.jbc.org/content/274/4/2225.full}}</ref> |
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While the exact signaling pathway of Bcl- |
While the exact signaling pathway of Bcl-xL is still not known, it is believed that Bcl-XL differs highly from Bcl-2 in the their mechanism of inducing apoptosis. A study was done where Bcl-XL was about ten times more functional than Bcl-2 when induced by the chemotherapy drug, [[Doxorubicin]].<ref>{{cite journal|last1=Fiebig|first1=Aline A.|last2=Et al|title=Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line|journal=BMC Cancer|date=August 23, 2006|volume=6|issue=213|doi=10.1186/1471-2407-6-213|url=http://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-6-213#Bib1}}</ref> Bcl-xL can specifically bind to cytochrome C residues, preventing apoptosis.<ref>{{cite journal|last1=Bertini|first1=Ivano|last2=Et al|title=The Anti-Apoptotic Bcl-xL Protein, a New Piece in the Puzzle of Cytochrome C Interactome|journal=PLOS One|date=April 18, 2011|doi=10.1371/journal.pone.0018329|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018329}}</ref> |
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[[Image:Signal transduction pathways.svg|300px|thumb|right|Overview of signal transduction pathways]] |
[[Image:Signal transduction pathways.svg|300px|thumb|right|Overview of signal transduction pathways]] |
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==Clinical Significance== |
==Clinical Significance== |
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Bcl- |
Bcl-xL dysfunction in mice can cause ineffective production of red blood cells, sever anemia, hemolysis, and death. This protein has also been shown as a requirement for heme production <ref>{{cite journal|last1=Rhodes|first1=Melissa M.|last2=et al|title=Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin|journal=Blood Journal|date=May 17, 2005|volume=106|issue=5|doi=10.1182/blood-2004-11-4344|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895223/}}</ref> 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]], a disease where there is an overproduction of erythrocytes.<ref>{{cite journal|last1=M|first1=Silva|last2=et al|title=Expression of Bcl-x in erythroid precursors from patients with polycythemia vera.|journal=New England Journal of Medicine|date=February 26, 1998|volume=338|issue=9|pages=564–571|doi=10.1056/NEJM199802263380902|url=https://www.ncbi.nlm.nih.gov/pubmed/9475763}}</ref> |
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== Effects == |
== Effects == |
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Revision as of 01:57, 20 November 2016
 | This article needs additional citations for verification. (November 2016) |
B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.[1]
Function
It is a well-established concept in the field of apoptosis 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), causing a pore to form, cytochrome c is released leading to initiation of caspase cascade leading to apoptotic events.[2]
While the exact signaling pathway of Bcl-xL is still not known, it is believed that Bcl-XL differs highly from Bcl-2 in the their mechanism of inducing apoptosis. A study was done where Bcl-XL was about ten times more functional than Bcl-2 when induced by the chemotherapy drug, Doxorubicin.[3] Bcl-xL can specifically bind to cytochrome C residues, preventing apoptosis.[4]
Clinical Significance
Bcl-xL dysfunction in mice can cause ineffective production of red blood cells, sever anemia, hemolysis, and death. This protein has also been shown as a requirement for heme production [5] 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, a disease where there is an overproduction of erythrocytes.[6]
Effects
Similar to Bcl-2, Bcl-xL has been implicated in the survival of cancer cells. Bcl-xL is known to be over-expressed in hematopoietic disorders such as polycythemia vera, where Jak2 mutations lead to over-activation of intracellular signaling molecules, such as Stat5, which lead to transcription of Bcl-xL gene.
Related proteins
Other Bcl-2 proteins include Bcl-2, Bcl-w, Bcl-xs, and Mcl-1.
References
- ^ Korsmeyer, Stanley J. (March 1995). "Regulators of Cell Death". Trends in Genetics. 11 (3): 101–105. doi:10.1016/S0168-9525(00)89010-1. Retrieved 5 November 2016.
- ^ Finucane, Deborah M.; et al. (January 22, 1999). "Bax-induced Caspase Activation and Apoptosis via Cytochromec Release from Mitochondria Is Inhibitable by Bcl-xL". The Journal of Biological Chemistry. 274: 2225–2233. doi:10.1074/jbc.274.4.2225.
{{cite journal}}: Explicit use of et al. in:|last2=(help)CS1 maint: unflagged free DOI (link) - ^ Fiebig, Aline A.; et al. (August 23, 2006). "Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line". BMC Cancer. 6 (213). doi:10.1186/1471-2407-6-213.
{{cite journal}}: Explicit use of et al. in:|last2=(help)CS1 maint: unflagged free DOI (link) - ^ Bertini, Ivano; et al. (April 18, 2011). "The Anti-Apoptotic Bcl-xL Protein, a New Piece in the Puzzle of Cytochrome C Interactome". PLOS One. doi:10.1371/journal.pone.0018329.
{{cite journal}}: Explicit use of et al. in:|last2=(help)CS1 maint: unflagged free DOI (link) - ^ Rhodes, Melissa M.; et al. (May 17, 2005). "Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin". Blood Journal. 106 (5). doi:10.1182/blood-2004-11-4344.
{{cite journal}}: Explicit use of et al. in:|last2=(help) - ^ M, Silva; et al. (February 26, 1998). "Expression of Bcl-x in erythroid precursors from patients with polycythemia vera". New England Journal of Medicine. 338 (9): 564–571. doi:10.1056/NEJM199802263380902.
{{cite journal}}: Explicit use of et al. in:|last2=(help)