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{{short description|Transmembrane molecule in the mitochondria}}
[[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]]


'''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|pmid=7732571}}</ref>
'''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 | vauthors = Korsmeyer SJ | title = Regulators of cell death | journal = Trends in Genetics | volume = 11 | issue = 3 | pages = 101–105 | date = March 1995 | pmid = 7732571 | doi = 10.1016/S0168-9525(00)89010-1 }}</ref>


==Function==
== 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 [[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 and apoptotic events.<ref>{{cite journal|last1=Finucane|first1=Deborah M.|display-authors=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|issue=4|pages=2225–2233|doi=10.1074/jbc.274.4.2225|pmid=9890985|doi-access=free}}</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 and apoptotic events.<ref>{{cite journal | vauthors = Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR | title = Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL | journal = The Journal of Biological Chemistry | volume = 274 | issue = 4 | pages = 2225–2233 | date = January 1999 | pmid = 9890985 | doi = 10.1074/jbc.274.4.2225 | doi-access = free }}</ref>


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]]<ref>{{cite journal|last1=Fiebig|first1=Aline A.|display-authors=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|page=213|doi=10.1186/1471-2407-6-213|pmid=16928273|pmc=1560389}}</ref> and can specifically bind to cytochrome C residues, preventing apoptosis.<ref>{{cite journal|last1=Bertini|first1=Ivano|display-authors=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|volume=6|issue=4|pages=e18329|pmc=3080137|pmid=21533126}}</ref> 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.<ref>{{cite journal|last1=Hu|first1=Yuanming|title=Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation|journal=Proceedings of the National Academy of Sciences of the United States of America|date=February 21, 1998|volume=95|issue=8|pages=4386–4391|doi=10.1073/pnas.95.8.4386|pmid=9539746|pmc=22498}}</ref>
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]]<ref>{{cite journal | vauthors = Fiebig AA, Zhu W, Hollerbach C, Leber B, Andrews DW | 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 | volume = 6 | issue = 213 | pages = 213 | date = August 2006 | pmid = 16928273 | pmc = 1560389 | doi = 10.1186/1471-2407-6-213 | doi-access = free }}</ref> and can specifically bind to cytochrome C residues, preventing apoptosis.<ref>{{cite journal | vauthors = Bertini I, Chevance S, Del Conte R, Lalli D, Turano P | title = The anti-apoptotic Bcl-x(L) protein, a new piece in the puzzle of cytochrome c interactome | journal = PLOS ONE | volume = 6 | issue = 4 | pages = e18329 | date = April 2011 | pmid = 21533126 | pmc = 3080137 | doi = 10.1371/journal.pone.0018329 | bibcode = 2011PLoSO...618329B | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Hu Y, Benedict MA, Wu D, Inohara N, Núñez G | title = Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 8 | pages = 4386–4391 | date = April 1998 | pmid = 9539746 | pmc = 22498 | doi = 10.1073/pnas.95.8.4386 | bibcode = 1998PNAS...95.4386H | doi-access = free }}</ref>


[[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]]


==Clinical significance==
==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<ref>{{cite journal|last1=Rhodes|first1=Melissa M.|display-authors=et al|title=Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin|journal=Blood|date=May 17, 2005|volume=106|issue=5|doi=10.1182/blood-2004-11-4344|pmid=15899920|pmc=1895223|pages=1857–1863}}</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|display-authors=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|pmid=9475763}}</ref>
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<ref>{{cite journal | vauthors = Rhodes MM, Kopsombut P, Bondurant MC, Price JO, Koury MJ | title = Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin | journal = Blood | volume = 106 | issue = 5 | pages = 1857–1863 | date = September 2005 | pmid = 15899920 | pmc = 1895223 | doi = 10.1182/blood-2004-11-4344 }}</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 | vauthors = Silva M, Richard C, Benito A, Sanz C, Olalla I, Fernández-Luna JL | title = Expression of Bcl-x in erythroid precursors from patients with polycythemia vera | journal = The New England Journal of Medicine | volume = 338 | issue = 9 | pages = 564–571 | date = February 1998 | pmid = 9475763 | doi = 10.1056/NEJM199802263380902 | doi-access = free }}</ref>


Similar to other Bcl-2 family members, Bcl-xL has been implicated in the survival of cancer cells by inhibiting the function of [[TP53|p53]], 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.<ref>{{cite journal|last1=AF|first1=Schott|title=Bcl-XL protects cancer cells from p53-mediated apoptosis|journal=Oncogene|date=1995|volume=11|issue=7|pages=1389–1394|pmid=7478561}}</ref>
Similar to other Bcl-2 family members, Bcl-xL has been implicated in the survival of cancer cells by inhibiting the function of [[TP53|p53]], 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.<ref>{{cite journal | vauthors = Schott AF, Apel IJ, Nuñez G, Clarke MF | title = Bcl-XL protects cancer cells from p53-mediated apoptosis | journal = Oncogene | volume = 11 | issue = 7 | pages = 1389–1394 | date = October 1995 | pmid = 7478561 }}</ref>


Bcl-xL is a target of various [[senolytic]] agents. Studies of cell cultures of senescent [[human umbilical vein endothelial cell]]s have shown that both [[fisetin]] and [[quercetin]] induce apoptosis by inhibition of Bcl-xL.<ref name="pmid32686219">{{cite journal | vauthors = Kirkland JL, Tchkonia T | title = Senolytic drugs: from discovery to translation | journal = [[Journal of Internal Medicine]] | date=2020 | doi = 10.1111/joim.13141| pmc=7405395 | pmid = 32686219}}</ref> Fisetin has roughly twice the senolytic potency as quercetin.<ref name="pmid32752135">{{cite journal | vauthors=Wyld L, Bellantuono I, Tchkonia T, Danson S, Kirkland JL | title=Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies | journal= [[Cancers (journal)|Cancers]]| volume=12 | issue=8 | pages=e2134 | year=2020 | doi = 10.3390/cancers12082134 | pmid=32752135| pmc=7464619 | doi-access=free }}</ref>
Bcl-xL is a target of various [[senolytic]] agents. Studies of cell cultures of senescent [[human umbilical vein endothelial cell]]s have shown that both [[fisetin]] and [[quercetin]] induce apoptosis by inhibition of Bcl-xL.<ref name="pmid32686219">{{cite journal | vauthors = Kirkland JL, Tchkonia T | title = Senolytic drugs: from discovery to translation | journal = Journal of Internal Medicine | volume = 288 | issue = 5 | pages = 518–536 | date = November 2020 | pmid = 32686219 | pmc = 7405395 | doi = 10.1111/joim.13141 }}</ref> Fisetin has roughly twice the senolytic potency as quercetin.<ref name="pmid32752135">{{cite journal | vauthors = Wyld L, Bellantuono I, Tchkonia T, Morgan J, Turner O, Foss F, George J, Danson S, Kirkland JL | display-authors = 6 | title = Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies | journal = Cancers | volume = 12 | issue = 8 | pages = e2134 | date = July 2020 | pmid = 32752135 | pmc = 7464619 | doi = 10.3390/cancers12082134 | doi-access = free }}</ref>

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. {{cn|date=September 2020}}


== Related proteins ==
== Related proteins ==
Other Bcl-2 proteins include [[Bcl-2]], [[Bcl-w]], Bcl-xs, and [[Mcl-1]].
Other Bcl-2 proteins include [[Bcl-2]], [[Bcl-w]], Bcl-xs, and [[Mcl-1]].


==References==
== References ==
{{Reflist}}
{{Reflist}}


Latest revision as of 21:39, 24 July 2024

X-ray crystal structure of Bcl-xL with 1.76 Å resolution

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

[edit]

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 and 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 their mechanism of inducing apoptosis. Bcl-xL is about ten times more functional than Bcl-2 when induced by the chemotherapy drug, Doxorubicin[3] and can specifically bind to cytochrome C residues, preventing apoptosis.[4] 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.[5]

Overview of signal transduction pathways

Clinical significance

[edit]

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[6] 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.[7]

Similar to other Bcl-2 family members, Bcl-xL has been implicated in the survival of cancer cells by inhibiting the function of p53, 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.[8]

Bcl-xL is a target of various senolytic agents. Studies of cell cultures of senescent human umbilical vein endothelial cells have shown that both fisetin and quercetin induce apoptosis by inhibition of Bcl-xL.[9] Fisetin has roughly twice the senolytic potency as quercetin.[10]

[edit]

Other Bcl-2 proteins include Bcl-2, Bcl-w, Bcl-xs, and Mcl-1.

References

[edit]
  1. ^ Korsmeyer SJ (March 1995). "Regulators of cell death". Trends in Genetics. 11 (3): 101–105. doi:10.1016/S0168-9525(00)89010-1. PMID 7732571.
  2. ^ Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (January 1999). "Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL". The Journal of Biological Chemistry. 274 (4): 2225–2233. doi:10.1074/jbc.274.4.2225. PMID 9890985.
  3. ^ Fiebig AA, Zhu W, Hollerbach C, Leber B, Andrews DW (August 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): 213. doi:10.1186/1471-2407-6-213. PMC 1560389. PMID 16928273.
  4. ^ Bertini I, Chevance S, Del Conte R, Lalli D, Turano P (April 2011). "The anti-apoptotic Bcl-x(L) protein, a new piece in the puzzle of cytochrome c interactome". PLOS ONE. 6 (4): e18329. Bibcode:2011PLoSO...618329B. doi:10.1371/journal.pone.0018329. PMC 3080137. PMID 21533126.
  5. ^ Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (April 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4386–4391. Bibcode:1998PNAS...95.4386H. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
  6. ^ Rhodes MM, Kopsombut P, Bondurant MC, Price JO, Koury MJ (September 2005). "Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin". Blood. 106 (5): 1857–1863. doi:10.1182/blood-2004-11-4344. PMC 1895223. PMID 15899920.
  7. ^ Silva M, Richard C, Benito A, Sanz C, Olalla I, Fernández-Luna JL (February 1998). "Expression of Bcl-x in erythroid precursors from patients with polycythemia vera". The New England Journal of Medicine. 338 (9): 564–571. doi:10.1056/NEJM199802263380902. PMID 9475763.
  8. ^ Schott AF, Apel IJ, Nuñez G, Clarke MF (October 1995). "Bcl-XL protects cancer cells from p53-mediated apoptosis". Oncogene. 11 (7): 1389–1394. PMID 7478561.
  9. ^ Kirkland JL, Tchkonia T (November 2020). "Senolytic drugs: from discovery to translation". Journal of Internal Medicine. 288 (5): 518–536. doi:10.1111/joim.13141. PMC 7405395. PMID 32686219.
  10. ^ Wyld L, Bellantuono I, Tchkonia T, Morgan J, Turner O, Foss F, et al. (July 2020). "Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies". Cancers. 12 (8): e2134. doi:10.3390/cancers12082134. PMC 7464619. PMID 32752135.
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