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]
X-ray crystal structure of Bcl-xL with 1.76 Å resolution
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
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]
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.[citation needed]
Related proteins
Other Bcl-2 proteins include Bcl-2, Bcl-w, Bcl-xs, and Mcl-1.
References
^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.
^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.
^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. PMC1560389. PMID 16928273.
^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. PMC3080137. PMID 21533126.
^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. PMC22498. PMID 9539746.
^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. PMC1895223. PMID 15899920.
^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.
^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.
^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. PMC7405395. PMID 32686219.
^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. PMC7464619. PMID 32752135.
January 30, 2023
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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 X ray crystal structure of Bcl xL with 1 76 A resolution Contents 1 Function 2 Clinical significance 3 Related proteins 4 ReferencesFunction EditIt 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 pathwaysClinical significance EditBcl 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 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 citation needed Related proteins EditOther Bcl 2 proteins include Bcl 2 Bcl w Bcl xs and Mcl 1 References Edit 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 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 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 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 Hu Y Benedict MA Wu D Inohara N Nunez 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 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 Silva M Richard C Benito A Sanz C Olalla I Fernandez 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 Schott AF Apel IJ Nunez G Clarke MF October 1995 Bcl XL protects cancer cells from p53 mediated apoptosis Oncogene 11 7 1389 1394 PMID 7478561 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 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 Retrieved from https en wikipedia org w index php title Bcl xL amp oldid 1067517356, wikipedia, wiki, book, books, library,
