B-cell lymphoma-extra large (Bcl-xL), encoded by theBCL2-like 1 gene, is a transmembrane molecule in themitochondria. It is a member of theBcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such ascytochrome c, which leads tocaspase activation and ultimately,programmed cell death.[1]
It is a well-established concept in the field ofapoptosis 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, ifBax andBak 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] Growth factor independence 1 (Gfi1) upregulates the expression of the pro-survival Bcl-2 family member Bcl-xL in hematopoietic system[6]
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[7] 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 containsGATA-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 inpolycythemia vera, a disease where there is an overproduction of erythrocytes.[8]
Similar to other Bcl-2 family members, Bcl-xL has been implicated in the survival of cancer cells by inhibiting the function ofp53, 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.[9]
Bcl-xL is a target of varioussenolytic agents. Studies of cell cultures of senescenthuman umbilical vein endothelial cells have shown that bothfisetin andquercetin induce apoptosis by inhibition of Bcl-xL.[10] Fisetin has roughly twice the senolytic potency as quercetin.[11]
Other Bcl-2 proteins includeBcl-2,Bcl-w, Bcl-xs, andMcl-1.