Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: BCL2
DO: 0050873;
Cytogenetic location: 18q21.33 Genomic coordinates (GRCh38): 18:63,123,346-63,320,090 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.33 | Leukemia/lymphoma, B-cell, 2 | 3 |
From a cell line studied by Pegoraro et al. (1984) that showed t(8;14) and t(14;18) translocations, which are characteristic of Burkitt lymphoma (see 113970) and follicular lymphoma (see 613024), respectively, Tsujimoto et al. (1984) derived a DNA clone that was specific for the t(14;18) translocation. The probe detected rearrangement of the homologous DNA segment in leukemic cells and in follicular lymphoma cells with the t(14;18) chromosome translocation but not in other neoplastic or normal B or T cells. Tsujimoto et al. (1984) concluded that the probe identified the BCL2 gene on chromosome 18q21 that was unrelated to known oncogenes and may be important in the pathogenesis of B-cell neoplasms with this translocation.
From a human common acute lymphoblastic leukemia cell line, Cleary et al. (1986) cloned cDNAs for BCL2. By nucleotide sequence analysis, they showed that the 6-kb BCL2 mRNA potentially encodes a 26-kD protein that is homologous to a predicted Epstein-Barr virus protein.
Tsujimoto and Croce (1986) determined that the first exon of BCL2 is transcribed into a 3.5-kb mRNA. This exon contains a splicing donor signal so that BCL2 mRNA is spliced to the second exon to produce a 5.5- and an 8.5-kb mRNA. The 5.5- and 3.5-kb mRNAs code for the BCL2 alpha and beta proteins, respectively, which are identical except for the C-terminal portion.
Tsujimoto et al. (1985) found that their most specific probe hybridized to cellular DNA from hamster and mouse under stringent conditions, indicating that at least part of the BCL2 gene is conserved across mammalian species as are many cellular oncogenes. Negrini et al. (1987) cloned the murine gene homologous to BCL2 in man.
BRAG1: A Spurious 'BCL2-related' Gene
Das et al. (1996) reported the isolation and molecular characterization of a novel Bcl2-related cDNA from a human glioma. They designated the gene BRAG1 for 'brain related apoptosis gene.' They gene showed extensive homology to the BCL2 family of genes. The gene was expressed in normal brain as a 4.5-kb transcript and as a 1.8-kb transcript in human gliomas, which suggested to the authors that it may be rearranged in these tumors. The open reading frame of the BRAG1 gene encoded a protein of 31 kD. Using a bacterial expression vector, Das et al. (1996) produced BRAG1 protein that was found to crossreact with a BCL2 monoclonal antibody, further suggesting structural and immunologic similarity to BCL2. In an erratum, the authors concluded that the gene in question was in fact from the genome of Escherichia coli and occurred as a contaminant in cDNA libraries.
Ngan et al. (1988) found immunoreactive BCL2 protein in the neoplastic cells of almost all follicular lymphomas, whereas no BCL2 protein was detected in follicles affected by nonneoplastic processes or in normal lymphoid tissue.
By means of immunolocalization studies, Hockenbery et al. (1990) demonstrated that BCL2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000. Overexpression of BCL2 blocks the apoptotic death of a pro-B-lymphocyte cell line. Thus, BCL2 is unique among protooncogenes, being localized in mitochondria and interfering with programmed cell death independent of promoting cell division.
Wang et al. (1996) showed that BCL2 can target the protein kinase RAF1 (164760) to the mitochondria. Active RAF1 improved BCL2-mediated resistance to apoptosis.
Vaux et al. (1988) undertook to determine the biologic effects of the BCL2 gene by introducing BCL2 cDNA into bone marrow cells. They found that BCL2 cooperated with MYC to promote proliferation of B-cell precursors, some of which became tumorigenic. Reed et al. (1988) also demonstrated the oncogenic potential of BCL2 by gene transfer.
Tsujimoto (1989) used Epstein-Barr virus-infected human lymphoblastoid B-cell lines transfected with BCL2 sequences and driven by the simian virus 40 promoter and enhancer to demonstrate that overproduction of the BCL2 protein results in a distinct cellular growth advantage. Nunez et al. (1989) demonstrated the protooncogene role of BCL2 in B-cell growth and B-cell neoplasm formation. ERV1 is separate from BCL2 (Croce, 1989).
Williams (1991) reviewed the evidence that BCL2 acts by inhibiting cell loss by apoptosis (programmed cell death) rather than by stimulating cell production. (The term apoptosis is derived from ancient Greek for 'falling off of tree leaves.') Fesus et al. (1991) reviewed molecular mechanisms of apoptosis.
Jacobson et al. (1993) showed that the action of BCL2 in protecting cells from apoptosis is not by altering mitochondrial function; they found that human mutant cell lines that lack mitochondrial DNA can still be induced to die by apoptosis and that they can be protected from apoptosis by the overexpression of BCL2. Migheli et al. (1994) performed a light-microscopic immunohistochemical analysis of BCL2 protein expression in autopsy specimens of human brain and spinal cord in normal, aged individuals and those who had suffered from neurodegenerative diseases. BCL2 was strongly enriched within lipofuscin and autophagic vacuoles of neurons, and glial and vascular cells. Deng and Podack (1993) showed that transcription of the BCL2 gene is downregulated by interleukin-2 (IL2; 147680) deprivation and upregulated by IL2 addition. Deregulated expression of BCL2 was found to prolong the survival of cells of the cytotoxic T-cell line CTLL2 in the absence of IL2. Hengartner and Horvitz (1994) presented evidence that the cell survival gene in Caenorhabditis elegans called ced-9 is a homolog of BCL2; thus, molecular mechanisms of programmed cell death have been conserved from nematodes to mammals.
Nunez et al. (1991) reported that this protooncogene maintains immune responsiveness. Transgenic mice overproducing Bcl2 showed long-term persistence of immunoglobulin-secreting cells and an extended lifetime for memory B cells. Through studies in transgenic mice, Sentman et al. (1991) and Strasser et al. (1991) concluded that modulation of BCL2 expression is 'a determinant of life and death in normal lymphocytes.'
In a review, Korsmeyer (1992) pointed out that the effects of deregulated BCL2 suggest that it does not qualify as either a category I (promoter of cell growth and proliferation) or category II (tumor suppressor) oncogene. Whereas the product of the fusion of the PML gene (102578) and the retinoic acid receptor-alpha gene (180240) and the product of the fusion of BCR (151410) and ABL (189980) represent perturbation of both genes contributing to pathogenesis, disruption of the normal expression of the BCL2 locus alone appears to contribute to the development of lymphoma (Frankel, 1993).
Ji et al. (1996) examined the promoter activities of the normal and translocated BCL2 alleles in the DHL-4 cell line with the t(14;18) translocation. They demonstrated that cAMP response-binding protein (CREB; 123810) binds to a cAMP response element (CRE) in the BCL2 5-prime flanking region of the translocated allele. Access to this CRE site is blocked in the normal BCL2 allele. They concluded that the CRE site of the translocated BCL2 allele functions as a positive regulatory site in t(14;18) lymphomas.
To investigate the relationship between apoptosis and the BCL2/BAX (600040) system in the human corpus luteum, Sugino et al. (2000) examined the frequency of apoptosis and expression of BCL2 and BAX in the corpus luteum during the menstrual cycle and in early pregnancy. Immunohistochemistry revealed BCL2 expression in the luteal cells in the midluteal phase and early pregnancy, but not in the regressing corpus luteum. In contrast, BAX immunostaining was observed in the regressing corpus luteum, but not in the midluteal phase or early pregnancy. The BCL2 mRNA levels in the corpus luteum during the menstrual cycle were highest in the midluteal phase and lowest in the regressing corpus luteum. In the corpus luteum of early pregnancy, BCL2 mRNA levels were significantly higher than those in the midluteal phase. In contrast, BAX mRNA levels were highest in the regressing corpus luteum and remarkably low in the corpus luteum of early pregnancy. When corpora lutea of the midluteal phase were incubated with CG (see 118850), CG significantly increased the mRNA and protein levels of BCL2 and significantly decreased those of BAX. Sugino et al. (2000) concluded that BCL2 and BAX may play important roles in the regulation of the life span of the human corpus luteum by controlling the rate of apoptosis.
Li et al. (2001) found increased levels of BAX and its mRNA in the stroma but not in the endothelium of Fuchs dystrophy (see 136800) corneas. Following exposure to camptothecin (a DNA synthesis inhibitor known to induce apoptosis in vitro), keratocytes from patients produced an increased level of BAX and a low level of BCL2 distinctly different from the response of normal keratocytes. The authors concluded that their results point to a disease-related disturbance in the regulation of apoptosis in Fuchs dystrophy. They proposed that excessive apoptosis might be an important mechanism in the pathogenesis of Fuchs dystrophy.
Vaskivuo et al. (2001) investigated the extent and localization of apoptosis in human fetal (aged 13 to 40 weeks) and adult ovaries. They also studied the expression of apoptosis-regulating proteins BCL2 and BAX. Expression of BCL2 was observed only in the youngest fetal ovaries (weeks 13 to 14), and BAX was present in the ovaries throughout the entire fetal period. In adult ovaries, apoptosis was detected in granulosa cells of secondary and antral follicles, and BCL2 and BAX were expressed from primary follicles onwards. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14 and 28, decreasing thereafter toward term.
McGill et al. (2002) performed microarray studies to identify MITF (156845)-dependent KIT (164920) transcriptional targets in primary human melanocytes. Among identified targets was BCL2, whose germline deletion produced melanocyte loss and exhibited phenotypic synergy with Mitf in mice. The regulation of BCL2 by MITF was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. MITF was found to regulate BCL2 in osteoclasts, and both Mitf mi/mi and Bcl2 -/- mice exhibited severe osteopetrosis. Disruption of MITF in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helped explain the vital roles of both MITF and BCL2 in the melanocyte lineage and the well-known treatment resistance of melanoma.
Marsden et al. (2002) established that the cell death pathway controlled by BCL2 does not require caspase-9 (602234) or its activator APAF1 (602233). In keeping with their evidence that neither is required for hematopoietic homeostasis, in which the BCL2 family has major roles, deletion of thymocytes with self-reactivity depends on BIM (603827) but not on APAF1. Because apoptosis was at most slightly delayed by the absence of APAF1 or caspase-9, Marsden et al. (2002) concluded that the apoptosome is not an essential trigger for apoptosis but is rather a machine for amplifying the caspase cascade. They found that BCL2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of APAF1 and caspase-9 did not. Caspase activity was still discernible in cells lacking APAF1 or caspase-9 and a potent caspase antagonist both inhibited apoptosis and retarded cytochrome c (123970) release. Marsden et al. (2002) concluded that BCL2 regulates a caspase activation program independently of the cytochrome c/APAF1/caspase-9 apoptosome, which seems to amplify rather than initiate the caspase cascade.
Lin et al. (2004) showed that BCL2 interacts with nuclear receptor NUR77 (NR4A1; 139139), which is required for cancer cell apoptosis induced by many antineoplastic agents. The interaction was mediated by the N-terminal loop region of BCL2 and was required for NUR77 mitochondrial localization and apoptosis. NUR77 binding induced a BCL2 conformational change that exposed its BH3 domain, resulting in conversion of BCL2 from a protector to a killer. These findings coupled NUR77 with the BCL2 apoptotic machinery and demonstrated that BCL2 can manifest opposing phenotypes, induced by interactions with proteins such as NUR77.
Using microarray analysis of gene expression signatures, Lossos et al. (2004) studied prediction of prognosis in diffuse large B-cell lymphoma (DLBCL; see 605027). In a univariate analysis, genes were ranked on the basis of their ability to predict survival; the strongest predictors of longer overall survival were LMO2 (180385), BCL6 (109565), and FN1 (135600), and the strongest predictors of shorter overall survival were CCND2 (123833), SCYA3 (182283), and BCL2. Lossos et al. (2004) developed a multivariate model that was based on the expression of these 6 genes, and validated the model in 2 independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power.
Nishimura et al. (2005) used melanocyte-tagged transgenic mice and aging human hair follicles to demonstrate that hair graying is caused by defective self-maintenance of melanocyte stem cells. This process is dramatically accelerated with BCL2 deficiency, which causes selective apoptosis of melanocyte stem cells, but not of differentiated melanocytes, within the niche at their entry into the dormant state. Furthermore, physiologic aging of melanocyte stem cells was associated with ectopic pigmentation or differentiation within the niche, a process accelerated by mutation of the melanocyte master transcriptional regulator MITF (156845).
Cimmino et al. (2005) determined that the first 9 nucleotides of microRNAs, miR15A (609703) and miR16-1 (609704), are complementary to bases in a central region of BCL2 cDNA. By miRNA microarray chip and Western blot analysis of CD5 (153340)-positive lymphocytes from 4 normal individuals, they found high levels of both miRNAs and low levels of BCL2 protein, whereas the majority of the 26 CLL (151400) samples examined expressed low miR15A and miR16-1 levels and high BCL2 protein levels. Overexpression of either miRNA did not affect BCL2 mRNA stability but regulated BCL2 expression at the posttranscriptional level, and overexpression of miR15A or miR16-1 in megakaryocytic leukemia cells induced apoptosis.
Lang et al. (2005) identified 3 BMYB (601415)-binding sites in a DNase I-hypersensitive site near the junction of exon 2 and intron 2 in the BCL2 gene. Antisense BMYB downregulated BCL2 and led to apoptosis of a BCL2-expressing B-cell line.
Del Gaizo Moore et al. (2007) described a novel assay using BH3 peptides to predict dependence on antiapoptotic proteins for tumor maintenance. This assay, which they called BH3 profiling, accurately predicted sensitivity to a BCL2 antagonist in primary chronic lymphocytic leukemia (CLL) cells and distinguished MCL1 (159552) from BCL2 dependence in myeloma cell lines. Sensitivity to the BCL2 antagonist in CLLs was due to the requirement that BCL2 sequester the proapoptotic protein BIM. The BCL2 antagonist displaced BIM from the BH3-binding pocket of BCL2, allowing BIM to activate BAX, which led to activation of the death program.
Hoyer-Hansen et al. (2007) showed that Ca(2+)-induced autophagy in mammalian cells utilized a signaling pathway that included CAMKK2, AMPK (PRKAA2; 600497), and mTOR (FRAP1; 601231). Ca(2+)-induced autophagy was inhibited by BCL2 but only when BCL2 was localized to the endoplasmic reticulum.
Binding of BCL2 to BECN1 (604378) reduces the capacity of BECN1 to induce autophagy. Ciechomska et al. (2009) targeted BCL2 to mitochondria or endoplasmic reticulum (ER) and induced apoptosis through chemical stimuli or TNF (191160). Using immunofluorescence and electron microscopy, as well as immunoprecipitation analysis, they found that coexpression of BCL2 with BECN1 usually resulted in BECN1, but not BECN1 lacking the BCL2-binding domain, following BCL2 to the appropriate organelle. Binding of BECN1 to BCL2 did not modify apoptosis, irrespective of BCL2 concentration, location, or apoptotic stimulus. Autophagy-mediated survival induced by Becn1 was ruled out as a mechanism through analysis of mouse Atg5 (604261) -/- cells. Ciechomska et al. (2009) concluded that, although BECN1 contains a BH3-only motif, typical of proapoptotic proteins, it has little or no role as a modulator of the antiapoptotic function of BCL2.
Pedrini et al. (2010) showed that the toxicity of mutant SOD1 (147450) relies on its spinal cord mitochondria-specific interaction with BCL2. Mutant SOD1 induced morphologic changes and compromised mitochondrial membrane integrity leading to the release of cytochrome c only in the presence of BCL2. In cells and in mouse and human spinal cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a conformational change in BCL2 that resulted in the exposure of its BH3 domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain failed to support mutant SOD1-mediated mitochondrial toxicity.
Qin et al. (2011) found that induction of MIR365 by oxidized low density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs) was concomitant with induction of apoptotic cell death and decreased expression of BCL2. Bioinformatic analysis identified BCL2 as a potential MIR365 target. Transfection of HUVECs with an MIR365 inhibitor dose-dependently attenuated the inhibitory effect of ox-LDL on BCL2 mRNA and protein expression and reduced the apoptotic response of cells to ox-LDL.
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 (600039) 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.
BCL2 inhibits the influx of adenine nucleotides through the mitochondrial outer membrane (Cang et al., 2015) and can act as an antiapoptotic oncogene. Upregulation of BCL2, as in t(14;18) translocations, can produce B-cell lymphomas by inhibiting apoptosis. Because BCL2 interacts with other proteins through its BH3 binding domain, there developed interest in identifying BH3 mimetics, several of which have been identified and tested in clinical trials. One, venetoclax or ABT-199, had a reported 79% response rate in a trial of patients with relapsed chronic lymphocytic leukemia (Roberts et al., 2016).
Tsujimoto and Croce (1986) showed that the BCL2 gene consists of at least 2 exons.
Silverman et al. (1990) isolated 2 YACs, each containing part of the 3-exon BCL2 gene and overlapping by 60 kb. They sought to take advantage of the high recombination frequency in yeast to induce physical recombination between the 2 clones. Analysis of resulting tetrads revealed a spore containing a single recombinant YAC of 800 kb. Further analysis showed that this recombined YAC contained the entire BCL2 gene of about 230 kb, without overt rearrangements or deletions.
Negrini et al. (1987) determined that the mouse Bcl2 gene is composed of 2 exons separated by more than 15 kb.
The BCL2 gene maps to chromosome 18q21 (Tsujimoto et al., 1984).
Negrini et al. (1987) mapped the mouse Bcl2 gene to chromosome 1. Mock et al. (1988) demonstrated linkage to markers on mouse chromosome 1 and concluded that Bcl2 is centromeric to the renin locus in that species.
From a young male with acute lymphoblastic leukemia, Pegoraro et al. (1984) established a cell line that showed an 8;14 and a 14;18 translocation, which are characteristic of Burkitt lymphoma and of follicular lymphoma, respectively. The cell line was Epstein-Barr virus antigen-negative, reacted with monoclonal antibodies specific for B cells and contained rearranged heavy and light chain genes, but did not express immunoglobulins. One of the J(H) segments of one of the 14q+ chromosomes was rearranged with a segment of chromosome 8, where the MYC gene (190080) is situated; the other 14q+ chromosome was rearranged with a segment of chromosome 18 where a putative oncogene they called BCL2 was thought to reside. The breakpoint in chromosome 18 was at q21. The translocated MYC gene was in its germline configuration and was located more than 14 kb from the chromosomal breakpoint.
Haluska et al. (1987) discussed a general hypothesis for the mechanism of chromosome translocation in B- and T-cell neoplasia. They suggested that it is a perversion of normal translocation processes; specifically in B-cell chronic lymphocytic leukemia, there appears to be involvement of the immunoglobulin V(D)J recombinase. There is, at 14q32 in IgH, a consensus that is mimicked by heptamer-nonamer sequences at 11q13, 18q21, and 8q24. In these areas are located cell growth factors BCL1, BCL2, and MYC, respectively.
Pegoraro et al. (1984) postulated 2 steps in the malignant process. First, the 14;18 translocation, occurring in an activated B cell and involving the excluded heavy chain allele on 14q32 and the BCL2 gene on chromosome 18, brought a heavy chain enhancer close to the BCL2 gene. Constitutive expression of BCL2 led to clonal expansion of t(14;18) cells and a relatively low-grade malignancy. Second, within the malignant clone of B cells, the t(8;14) translocation occurred, leading to high-grade malignancy through activation of MYC. Mufti et al. (1983) reported a double translocation of the same type in a case of acute leukemia.
From the cell line studied by Pegoraro et al. (1984), Tsujimoto et al. (1984) derived a DNA clone that was specific for chromosome 18. and was flanked by the heavy chain joining (J) region of the immunoglobulin heavy chain locus (147100) on chromosome 14--thus, it was derived from the breakpoint on chromosome 18 involved in the creation of the t(14;18)(q32;q21). This probe detected rearrangement of the homologous DNA segment in the leukemic cells and in follicular lymphoma cells with the t(14;18) chromosome translocation but not in other neoplastic or normal B or T cells. These workers concluded that the probe identifies BCL2, a gene locus on 18q21 that is unrelated to known oncogenes and may be important in the pathogenesis of B-cell neoplasms with this translocation.
Bakhshi et al. (1985) also cloned the breakpoints of t(14;18) in 4 cases. The breakpoints clustered within a 4.3-kb region on chromosome 18. The breakpoint on chromosome 14 brought the Ig enhancer region close to a newly identified transcriptional unit on 18q21. Since none of the oncogenes are known to map to 18q21, cloning this element may provide an opportunity to characterize a new transforming gene.
Tsujimoto et al. (1985) showed that about 60% of the breakpoints on chromosome 18 in cases of t(14;18) translocation are tightly clustered in the 3-prime noncoding region of the BCL2 gene and about 10% are clustered at a region 3-prime to the BCL2 gene. From analysis of a panel of follicular lymphoma DNAs with probes for the first exon of the BCL2 gene, Tsujimoto et al. (1987) showed that DNA rearrangements may also occur 5-prime to the involved BCL2 gene.
Cleary et al. (1986) determined that most 14;18 translocation breakpoints cluster within a narrow region of a 5.4-kb exon that contains a long 3-prime untranslated region of the BCL2 mRNA. As a result of the translocation, hybrid BCL2/immunoglobulin heavy chain transcripts are produced that consist of the 5-prime half of the BCL2 mRNA fused to a 'decapitated' immunoglobulin heavy chain mRNA. Nucleotide sequence analyses confirmed that the hybrid transcripts continue to encode a normal BCL2 protein. Bakhshi et al. (1987) concluded that immunoglobulin recombinase plays no role in the chromosome 18 breakage. Instead, a direct repeat duplication of chromosome 18 sequences was discovered at both chromosomal junctures, typical of the repair of a naturally occurring staggered double-stranded DNA break. The translocation in t(14;18) occurs in a B cell as an illegitimate recombination at the first step in the rearrangement of the heavy chain gene cluster, the step in which D(H) is fused to J(H)--see 146910 and 147010.
By Southern blot analysis in cases of non-Hodgkin lymphoma, Aisenberg et al. (1988) found frequent rearrangement of the BCL2 gene.
DiCroce and Krontiris (1995) observed that most translocations involving BCL2 are very narrowly targeted to 3 breakpoint clusters evenly spaced over a 100-bp region of the gene's terminal exon. The immediate upstream boundary of this major breakpoint region (MBR) is a specific recognition site for single-strand DNA (ssDNA) binding proteins on the sense and antisense strands. The downstream flank of the MBR is a helicase binding site. DiCroce and Krontiris (1995) demonstrated that the helicase and ssDNA binding proteins show reciprocal changes in binding activity over the cell cycle. The helicase is maximally active in G1 and early S phases; the ssDNA binding proteins are maximally active in late S and G2/M phases. One component of the helicase binding complex is the Ku antigen (152690). Thus, the authors showed that a protein with helicase activity implicated in repair of double-strand breaks, V(D)J recombination, and, potentially, cell cycle regulation is targeted to the BCL2 MBR.
Raghavan et al. (2004) reproduced key features of the chromosome 14;18 translocation process on an episome that propagates in human cells. The RAG complex, which consists of the RAG1 (179615) and RAG2 (179616) proteins, is the normal enzyme for DNA cleavage at V, D, or J segments. It nicks the BCL2 major breakpoint region, which is confined to a 150-bp segment, both in vitro and in vivo in a manner that reflects the pattern of the chromosomal translocations. However, the BCL2 major breakpoint region is not a V(D)J recombination signal; rather, it assumes a non-B-form DNA structure within the chromosomes of human cells at 20 to 30% of alleles. Purified DNA assuming this structure contains stable regions of single-strandedness, which correspond well to the translocation regions in patients. Raghavan et al. (2004) concluded that a stable non-B-DNA structure in the human genome appears to be the basis for the fragility of the BCL2 major breakpoint region, and that the RAG complex is able to cleave this structure.
Nakayama et al. (1994) reported results from the study of BCL2-deficient mice created through the injection of clones containing 1 mutated bcl2 allele into C57BL/6 blastocysts to generate chimeric mice. Animals homozygous for the mutation were smaller but viable, although about half of them died by 6 weeks of age. As shown earlier with somatic bcl2 gene-targeted mice, the number of lymphocytes markedly decreased within a few weeks after birth while other hematopoietic lineages remained unaffected. Among lymphocytes, CD8(+) T cells disappeared most quickly followed by CD4(+) T cells, whereas B cells were least affected. The homozygously defective lymphocytes could, however, respond normally to various stimuli including anti-CD3, Con A, interleukin-2, lipopolysaccharide, and anti-IgM antibody. Abnormalities in nonlymphoid organs included smaller auricles, hair color turning gray at 4 to 5 weeks of age, and polycystic kidney disease-like change of renal tubules. These results suggested that bcl2 may be involved during morphogenesis where inductive interactions between epithelium and mesenchyme are important such as in the kidneys, hair follicles, and perichondrium of auricles. Surprisingly, the nervous system, intestines, and skin appeared normal despite the fact that these organs show high levels of endogenous bcl2 expression in normal mice.
McDonnell et al. (1989) found that transgenic mice bearing a bcl2-immunoglobulin minigene that mimicked the t(14;18) translocation displayed a polyclonal follicular hyperplasia with a 4-fold increase in resting B cells. B cells accumulated because of extended cell survival rather than increased proliferation.
By crossing mice with motoneuron disease (pmn) with mice that overexpressed Bcl2, Sagot et al. (1995) demonstrated rescue of facial motoneurons with restoration of normal soma size and expression of choline acetyltransferase. However, Bcl2 overexpression did not prevent degeneration of myelinated axons and did not increase the life span of the animals.
Apoptosis of photoreceptors occurs infrequently in adult retina and can be triggered in inherited and environmentally induced retinal degenerations. BCL2 is known to be a potent regulator of cell survival in neurons. Chen et al. (1996) created lines of transgenic mice overexpressing Bcl2 to test for its ability to increase photoreceptor survival. They found that Bcl2 increased photoreceptor survival in 3 mouse models: a line of transgenic mice expressing a C-terminal truncated form of rhodopsin (180380) associated with rapid degeneration of photoreceptors; homozygous rd mice with nonfunctional rod-cGMP-phosphodiesterase (see 180071); and albino mice exposed to sustained illumination. Bcl2 increased photoreceptor survival in the first 2 mouse models and decreased the damaging effects of constant light exposure in the albino mice. Apoptosis was induced in normal photoreceptors by very high levels of Bcl2. Chen et al. (1996) concluded that Bcl2 is an important regulator of photoreceptor cell death in retinal degenerations.
Martinou et al. (1994) generated transgenic mice in which neurons overexpress the human BCL2 protein under control of neuron-specific enolase or phosphoglycerate kinase promoters. These transgenic mice had reduced neuronal loss during the period of naturally occurring cell death with a resulted hypertrophy of the nervous system. The facial nucleus and the ganglion cell layer of the retina had 40 to 50% more neurons than in control animals. In addition, these transgenic mice were more resistant to ischemic damage induced by middle cerebral artery occlusion than were control mice.
Farlie et al. (1995) reported observations in transgenic mice expressing BCL2 under the control of the neuron-specific enolase promoter, suggesting that the role of BCL2 is wider than merely its role in lymphocytes. Sensory neurons isolated from dorsal ganglia of newborn mice normally require nerve growth factor for their survival in culture, but those from the BCL2 transgenic mice showed enhanced survival in its absence. Furthermore, apoptotic death of motor neurons after axotomy of the sciatic nerve was inhibited in these mice. The number of neurons in the 2 neuronal populations from the central and peripheral nervous system was increased by 30%, indicating that BCL2 expression can protect neurons from cell death during development. Thus, BCL2 may play an important role in survival of neurons both during development and throughout adult life.
The V(D)J recombinase has been suspected to play a role in non-Hodgkin lymphomas (Haluska et al., 1987). Vanasse et al. (1999) studied lymphomas in mice with severe combined immunodeficiency and p53 null mutations (SCIDp53-/- mice). These tumors were most likely in the pro-B-cell stage. The majority carried t(12;15) translocations, the breakpoints of which involved the IgH locus, indicating that the translocation occurred as a result of aberrant rejoining of IgH loci cleaved during attempted V(D)J recombination at the pro-B-cell stage. These results suggested that the oncogenic potential inherent in antigen receptor diversification is controlled in vivo by efficient rejoining of DNA ends generated during V(D)J recombination.
To determine the influence of BCL2 on the development of myocytes, Limana et al. (2002) analyzed the population dynamics of this cell type in the heart of transgenic mice overexpressing BCL2 under the control of the alpha-myosin heavy chain promoter. Transgenic mice and wildtype mice were studied for periods up to 4 months after birth. BCL2 overexpression produced a significant increase in the percentage of cycling myocytes and their mitotic index. By several measures, the authors demonstrated a replication-enhancing function of BCL2 in myocytes in vivo in the absence of stressful conditions.
Dominov et al. (2005) generated mdx (300377) or Lama2 (156225)-null mice that also overexpressed muscle-specific human BCL2. In mdx mice, overexpression of BCL2 failed to produce any significant differences in muscle pathology; however, in Lama2-null mice, muscle-specific overexpression of BCL2 led to a several-fold increase in life span and an increased growth rate. Dominov et al. (2005) concluded that BCL2-mediated apoptosis appeared to play a significant role in pathogenesis of congenital muscular dystrophy type 1A (607855) due to LAMA2 deficiency but not in Duchenne muscular dystrophy (DMD; 310200) due to dystrophin deficiency.
He et al. (2012) showed that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, the authors generated mutant mice that showed normal levels of basal autophagy but were deficient in stimulus (exercise- or starvation)-induced autophagy. These mice, termed BCL2 AAA mice, contain knockin mutations in BCL2 phosphorylation sites (thr69ala, ser70ala, and ser84ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 (604378) complex and autophagy activation. BCL2 AAA mice showed decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high fat diet-induced glucose intolerance. Thus, He et al. (2012) suggested that exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
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