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HGNC Approved Gene Symbol: BCL2L1
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:31,664,452-31,723,963 (from NCBI)
Boise et al. (1993) isolated a BCL2 (151430)-related gene, which they designated BCLX, and showed that it can function as a BCL2-independent regulator of programmed cell death (apoptosis). Alternative splicing resulted in 2 distinct BCLX mRNAs. The protein product of the larger mRNA (BCLXL) was similar in size and predicted structure to BCL2. When stably transfected into an IL3-dependent cell line, it inhibited cell death upon growth factor withdrawal at least as well as BCL2. Unexpectedly, the smaller mRNA species (BCLXS) encodes a protein that inhibits the ability of BCL2 to enhance the survival of growth factor-deprived cells. In vivo, the smaller BCLX mRNA was expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, the large form of BCLX was found in tissues containing long-lived postmitotic cells, such as adult brain. Together these data suggested that BCLX plays an important role in both positive and negative regulation of programmed cell death. Boise et al. (1993) found that BCLX is highly conserved in vertebrate evolution.
By microarray analysis, Jun et al. (2001) demonstrated expression of the BCL2L1 gene in human donor corneas.
Vander Heiden et al. (1997) observed in Jurkat cells that a wide variety of apoptotic and necrotic stimuli induce progressive mitochondrial swelling and outer mitochondrial membrane rupture. Discontinuity of the outer mitochondrial membrane results in cytochrome c redistribution from the intermembrane space to the cytosol, followed by subsequent inner mitochondrial membrane depolarization. The mitochondrial membrane protein BCLX could inhibit these changes in cells treated with apoptotic stimuli. In addition, BCLX-expressing cells adapt to growth factor withdrawal or staurosporine treatment by maintaining a decreased mitochondrial membrane potential. BCLX expression also prevents mitochondrial swelling in response to agents that inhibit oxidative phosphorylation. These data suggested to Vander Heiden et al. (1997) that BCLX promotes cell survival by regulating the electrical and osmotic homeostasis of mitochondria.
Silva et al. (1998) found that erythroid cells from patients with polycythemia vera (263300) survived in vitro without erythropoietin. This finding correlated with the expression of BCLX protein, even in mature erythroblasts that normally do not express BCLX. The large BCLX mRNA was the predominant form detected in the erythropoietin-independent erythroid cells. They concluded that deregulated expression of BCLX may contribute to the erythropoietin-independent survival of erythroid-lineage cells in polycythemia vera and thereby contribute to the pathogenesis of this disorder. Moliterno et al. (1998) simultaneously reported impaired expression of the thrombopoietin receptor (MPL; 159530) by platelets from patients with polycythemia vera.
During transduction of an apoptotic signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases (see 147678). The BCL2 family of proteins, whose members may be antiapoptotic or proapoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis. Shimizu et al. (1999) created liposomes that carried the mitochondrial porin channel VDAC (604492) to show that the recombinant proapoptotic proteins Bax (600040) and Bak (600516) accelerate the opening of VDAC, whereas the antiapoptotic protein BCLXL closes VDAC by binding to it directly. Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by BCLXL. In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by BCLXL. Shimizu et al. (1999) concluded that the BCL2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.
The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. Deverman et al. (2002) showed that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of 2 asparagines in the unstructured loop of BCLXL. Deamidation of these asparagines imparted susceptibility to apoptosis by disrupting the ability of BCLXL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, BCLXL deamidation was actively suppressed in fibroblasts, and suppression of deamidation was an essential component of their resistance to DNA damage-induced apoptosis. The authors concluded that regulation of BCLXL deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents.
Kanauchi et al. (2003) examined whether apoptosis-regulating genes, BCLXL and FAS (134637), and the telomere-related gene TERF1 (600951) differ in expression between adrenal cortical cancers and benign adrenal tumors. Tissues from 4 adrenal cortical cancers were compared with 7 normal adrenal tissues, 17 cortical adenomas, 4 cortical hyperplasias, and 20 pheochromocytomas for expressions of BCLXL and FAS by RT-PCR, and for expressions of TERF1 by real-time quantitative RT-PCR. All benign adrenal tissues expressed both the antiapoptosis gene BCLXL and the proapoptosis gene FAS, but the adrenal cortical cancers expressed only BCLXL and not FAS.
The p53 (191170) gene product functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic BCL2 (151430) proteins to permeabilize mitochondria and initiate apoptosis. Chipuk et al. (2005) demonstrated that a tripartite nexus between BCLXL, cytoplasmic p53, and PUMA (605854) coordinates these distinct p53 functions. After genotoxic stress, BCLXL sequestered cytoplasmic p53. Nuclear p53 caused expression of PUMA, which then displaced p53 from BCLXL, allowing p53 to induce mitochondrial permeabilization. Mutant BCLXL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, Chipuk et al. (2005) concluded that PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53.
Bivona et al. (2006) found that the subcellular localization and function of Kras (see KRAS2; 190070) in mammalian cells was modulated by Pkc (see 176960). Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl. Phosphorylated Kras required Bclxl for induction of apoptosis.
Fonseca-Pereira et al. (2014) showed that the neurotrophic factor receptor RET (164761) drives hematopoietic stem cell (HSC) survival, expansion, and function. Strikingly, RET signals provide HSCs with critical BCL2 and BCL2L1 surviving cues, downstream of p38 MAP kinase (MAPK14; 600289) and CREB (123810) activation. Accordingly, enforced expression of the RET downstream targets BCL2 or BCL2L1 is sufficient to restore the activity of RET-null progenitors in vivo. Activation of RET results in improved HSC survival, expansion, and in vivo transplantation efficiency. Human cord blood progenitor expansion and transplantation is also improved by neurotrophic factors, opening the way for exploration of RET agonists in human HSC transplantation. Fonseca-Pereira et al. (2014) concluded that their work showed that neurotrophic factors are novel components of the HSC microenvironment, revealing that hematopoietic stem cells and neurons are regulated by similar signals.
Hellmuth and Stemmann (2020) showed that human cells that enter mitosis with already active separase (ESPL1; 604143) rapidly undergo death in mitosis owing to direct cleavage of antiapoptotic MCL1 (159552) and BCLXL by separase. Cleavage not only prevents MCL1 and BCLXL from sequestering proapoptotic BAK (600516), but also converts them into active promoters of death in mitosis. The data strongly suggested that the deadliest cleavage fragment, the C-terminal half of MCL1, forms BAK/BAX (600040)-like pores in the mitochondrial outer membrane. MCL1 and BCLXL are turned into separase substrates only upon phosphorylation by NEK2A (604043). Early mitotic degradation of this kinase is therefore crucial for preventing apoptosis upon scheduled activation of separase in metaphase. Speeding up mitosis by abrogation of the spindle assembly checkpoint (SAC) results in a temporal overlap of the enzymatic activities of NEK2A and separase and consequently in cell death. Hellmuth and Stemmann (2020) proposed that NEK2A and separase jointly check on SAC integrity and eliminate cells that are prone to chromosome missegregation owing to accelerated progression through early mitosis.
Hartz (2014) mapped the BCL2L1 gene to chromosome 20q11.21 based on an alignment of the BCL2L1 sequence (GenBank BX647525) with the genomic sequence (GRCh38).
The article by DeOcesano-Pereira et al. (2014) describing a gene that regulates the splicing of BCLX, causing expression of the apoptotic BCLXS transcript, was retracted.
Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Miura, J., Wiener, H. H., Wright, L., Saba, S. G., Yim, D., Fein, A., Perez de Castro, I., Li, C., Thompson, C. B., Cox, A. D., Philips, M. R. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-X(L) on mitochondria and induces apoptosis. Molec. Cell 21: 481-493, 2006. [PubMed: 16483930] [Full Text: https://doi.org/10.1016/j.molcel.2006.01.012]
Boise, L. H., Gonzalez-Garcia, M., Postema, C. E., Ding, L., Lindsten, T., Turka, L. A., Mao, X., Nunez, G., Thompson, C. B. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597-608, 1993. [PubMed: 8358789] [Full Text: https://doi.org/10.1016/0092-8674(93)90508-n]
Chipuk, J. E., Bouchier-Hayes, L., Kuwana, T., Newmeyer, D. D., Green, D. R. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309: 1732-1735, 2005. [PubMed: 16151013] [Full Text: https://doi.org/10.1126/science.1114297]
DeOcesano-Pereira, C., Amaral, M. S., Parreira, K. S., Ayupe, A. C., Jacysyn, J. F., Amarante-Mendes, G. P., Reis, E. M., Verjovski-Almeida, S. Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis. Nucleic Acids Res. 42: 8343-8355, 2014. Note: Retraction: Nucleic Acids Res. 44: 9518 only, 2016. [PubMed: 24992962] [Full Text: https://doi.org/10.1093/nar/gku561]
Deverman, B. E., Cook, B. L., Manson, S. R., Niederhoff, R. A., Langer, E. M., Rosova, I., Kulans, L. A., Fu, X., Weinberg, J. S., Heinecke, J. W., Roth, K. A., Weintraub, S. J. Bcl-x(L) deamidation is a critical switch in the regulation of the response to DNA damage. Cell 111: 51-62, 2002. Note: Erratum: Cell: 115: 503 only, 2003. [PubMed: 12372300] [Full Text: https://doi.org/10.1016/s0092-8674(02)00972-8]
Fonseca-Pereira, D., Arroz-Madeira, S., Rodrigues-Campos, M., Barbosa, I. A. M., Domingues, R. G., Bento, T., Almeida, A. R. M., Ribeiro, H., Potocnik, A. J., Enomoto, H., Veiga-Fernandes, H. The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514: 98-101, 2014. [PubMed: 25079320] [Full Text: https://doi.org/10.1038/nature13498]
Hartz, P.A. Personal Communication. Baltimore, Md. 9/19/2014.
Hellmuth, S., Stemmann, O. Separase-triggered apoptosis enforces minimal length of mitosis. Nature 580: 542-547, 2020. [PubMed: 32322059] [Full Text: https://doi.org/10.1038/s41586-020-2187-y]
Jun, A. S., Liu, S. H., Koo, E. H., Do, D. V., Stark, W. J., Gottsch, J. D. Microarray analysis of gene expression in human donor corneas. Arch. Ophthal. 119: 1629-1634, 2001. [PubMed: 11709013] [Full Text: https://doi.org/10.1001/archopht.119.11.1629]
Kanauchi, H., Wada, N., Ginzinger, D. G., Yu, M., Wong, M. G., Clark, O. H., Duh, Q.-Y. Diagnostic and prognostic value of Fas and telomeric-repeat binding factor-1 genes in adrenal tumors. J. Clin. Endocr. Metab. 88: 3690-3693, 2003. [PubMed: 12915656] [Full Text: https://doi.org/10.1210/jc.2002-020965]
Moliterno, A. R., Hankins, W. D., Spivak, J. L. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. New Eng. J. Med. 338: 572-580, 1998. [PubMed: 9475764] [Full Text: https://doi.org/10.1056/NEJM199802263380903]
Shimizu, S., Narita, M., Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 483-487, 1999. Note: Erratum: Nature 407: 767 only, 2000. [PubMed: 10365962] [Full Text: https://doi.org/10.1038/20959]
Silva, M., Richard, C., Benito, A., Sanz, C., Olalla, I., Fernandez-Luna, J. L. Expression of Bcl-x in erythroid precursors from patients with polycythemia vera. New Eng. J. Med. 338: 564-571, 1998. [PubMed: 9475763] [Full Text: https://doi.org/10.1056/NEJM199802263380902]
Vander Heiden, M. G., Chandel, N. S., Williamson, E. K., Schumacker, P. T., Thompson, C. B. Bcl-X(L) regulates the membrane potential and volume homeostasis of mitochondria. Cell 91: 627-637, 1997. [PubMed: 9393856] [Full Text: https://doi.org/10.1016/s0092-8674(00)80450-x]