Bcl-xL

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 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 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. Growth factor independence 1 (Gfi1) upregulates the expression of the pro-survival Bcl-2 family member Bcl-xL in hematopoietic system. Its expression is upregulated by Gfi1 via Hemgn to promote cell survival. {{cite journal

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, 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, 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 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. Fisetin has roughly twice the senolytic potency as quercetin.

Related proteins

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

References

References

1. (March 1995). "Regulators of cell death". Trends in Genetics.
2. (January 1999). "Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL". The Journal of Biological Chemistry.
3. (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.
4. (April 2011). "The anti-apoptotic Bcl-x(L) protein, a new piece in the puzzle of cytochrome c interactome". PLOS ONE.
5. (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.
6. (May 2025). "Bcl-xL is important for the antiapoptotic activity of Gfi1 and is upregulated by Gfi1 through hemgn". Journal of Immunology.
7. (September 2005). "Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin". Blood.
8. (February 1998). "Expression of Bcl-x in erythroid precursors from patients with polycythemia vera". The New England Journal of Medicine.
9. (October 1995). "Bcl-XL protects cancer cells from p53-mediated apoptosis". Oncogene.
10. (November 2020). "Senolytic drugs: from discovery to translation". Journal of Internal Medicine.
11. (July 2020). "Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies". Cancers.