 |
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
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 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]. NMR stidues show that Bcl-XL can specifically bind to cytochrome C, with interactions of residues, preventing apoptosis [4].
Clinical Significance
editBcl-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
editSimilar 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
editOther Bcl-2 proteins include Bcl-2, Bcl-w, Bcl-xs, and Mcl-1.
References
edit- ^ 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)
Category:Mitochondria Category:Cancer research Category:Apoptosis Category: Bcl-2