Bcl-xL

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]

## Contents

* 1 Function
* 2 Clinical significance
* 3 Related proteins
* 4 References

## 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.[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. Its expression is upregulated by Gfi1 via Hemgn to promote cell survival. [6][7]

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[8] 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.[9]

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.[10]

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.[11] Fisetin has roughly twice the senolytic potency as quercetin.[12]

## Related proteins

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

## References

1. ↑ "Regulators of cell death". Trends in Genetics 11 (3): 101–105. March 1995. doi:10.1016/S0168-9525(00)89010-1. PMID 7732571.
2. ↑ "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. January 1999. doi:10.1074/jbc.274.4.2225. PMID 9890985.
3. ↑ "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. August 2006. doi:10.1186/1471-2407-6-213. PMID 16928273.
4. ↑ "The anti-apoptotic Bcl-x(L) protein, a new piece in the puzzle of cytochrome c interactome". PLOS ONE 6 (4). April 2011. doi:10.1371/journal.pone.0018329. PMID 21533126. Bibcode: 2011PLoSO...618329B.
5. ↑ "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. April 1998. doi:10.1073/pnas.95.8.4386. PMID 9539746. Bibcode: 1998PNAS...95.4386H.
6. ↑ G C, Binod; Du, Pei; Zhang, Yangyang; Yang, Li; Dong, Fan (May 2025). "Bcl-xL is important for the antiapoptotic activity of Gfi1 and is upregulated by Gfi1 through hemgn". Journal of Immunology 214 (5): 1046–1058. doi:10.1093/jimmun/vkae066. PMID 40262274.
7. ↑ G C, Binod; Hoyt, Laura J.; Dovat, Sina; Dong, Fang (2024). "Upregulation of nuclear protein Hemgn by transcriptional repressor Gfi1 through repressing PU.1 contributes to the anti-apoptotic activity of Gfi1". Journal of Biological Chemistry 300 (11): 107860. doi:10.1016/j.jbc.2024.107860. https://www.sciencedirect.com/science/article/pii/S0021925824007782.
8. ↑ "Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin". Blood 106 (5): 1857–1863. September 2005. doi:10.1182/blood-2004-11-4344. PMID 15899920.
9. ↑ "Expression of Bcl-x in erythroid precursors from patients with polycythemia vera". The New England Journal of Medicine 338 (9): 564–571. February 1998. doi:10.1056/NEJM199802263380902. PMID 9475763.
10. ↑ "Bcl-XL protects cancer cells from p53-mediated apoptosis". Oncogene 11 (7): 1389–1394. October 1995. PMID 7478561.
11. ↑ "Senolytic drugs: from discovery to translation". Journal of Internal Medicine 288 (5): 518–536. November 2020. doi:10.1111/joim.13141. PMID 32686219.
12. ↑ "Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies". Cancers 12 (8). July 2020. doi:10.3390/cancers12082134. PMID 32752135.

* v
* t
* e

Apoptosis signaling pathway

Fas path|

| Ligand|

* Fas ligand

|

Receptor|

* Fas receptor

Intracellular|

* Death-inducing signaling complex

* DAXX
* ASK1

* FADD
* Caspase 8
* BID

* Cytochrome c
* Caspase 9
* Caspase 3

Pro-apoptotic:
BAX
BAK1/Bcl-2 homologous antagonist killer
Bcl-2-associated death promoter

Anti-apoptotic:
Bcl-2
Bcl-xL

TNF path|

| Ligand|

* Tumor necrosis factor alpha

|

Receptor|

* Tumor necrosis factor receptor 1
* Tumor necrosis factor receptor 2

Intracellular|

* TRADD

* FADD
* Caspase 8
* Caspase 3
* BID

* TRAF2
* ASK-1
* MEKK1
* IKK
* IκBα
* MKK7
* JNK
* NF-κB

Other|

| Intracellular|

IAPs
XIAP
NAIP
Survivin
c-IAP-1
c-IAP-2

* Apoptosis-inducing factor

|

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