Alternative titles; symbols
HGNC Approved Gene Symbol: BCL2L13
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:17,628,877-17,730,855 (from NCBI)
BCL2L13 is a proapoptotic mitochondrial BCL2 (151430) family protein (Kataoka et al., 2001).
Kataoka et al. (2001) identified human BCL2L13, which they called BCL-RAMBO, by database analysis and cloned the full-length cDNA. The predicted 485-amino acid protein has a calculated molecular mass of 55 kD. It has 4 BCL2 homology (BH) motifs and a C-terminal transmembrane anchor domain. The BH motifs and transmembrane anchor are separated by a stretch of more than 250 amino acids, including 2 short tandem repeats, that the authors termed the BHNo domain. Northern blot analysis detected a 4.1-kb BCL-RAMBO transcript in all human tissues and cell lines studied, with highest expression in heart, pancreas, and placenta. Weak expression of 2.1- and 1.2-kb transcripts was also detected, suggesting possible alternative splicing. Human BCL-RAMBO localized to mitochondria in transfected HeLa cells.
Yi et al. (2003) cloned a BCL-RAMBO splice variant that they termed BCL-RAMBO-beta from a human lymph node cDNA library. Compared with full-length BCL-RAMBO, BCL-RAMBO-beta contains a 98-bp insertion derived from an Alu element after exon 2 and lacks exons 4 and 5. The predicted 104-amino acid BCL-RAMBO-beta protein has only 1 BH domain and lacks the BHNo and membrane anchor domains. PCR analysis showed coexpression of BCL-RAMBO and BCL-RAMBO-beta in human tissues.
Kataoka et al. (2001) determined that the BCL2L13 gene contains 6 coding exons.
By database analysis, Kataoka et al. (2001) mapped the BCL2L13 gene to chromosome 22q11.
Using immunoprecipitation analysis, Kataoka et al. (2001) showed that human BCL-RAMBO did not interact with other BCL2 members to form heterodimers. Overexpression of BCL-RAMBO in 293T cells induced significant caspase-3 (600636) activation and cell death. Truncation analysis revealed that transmembrane domain and BHNo domain were important for BCL-RAMBO proapoptotic activity. Mitochondrial damage was observed during BCL-RAMBO-induced cell death, and cell death was specifically blocked by caspase inhibitors, IAPs (see 300079).
Yi et al. (2003) showed that overexpression of BCL-RAMBO-beta promoted etoposide- and Taxol-induced death in HeLa cells and 293A cells through the mitochondrial pathway, even though BCL-RAMBO-beta did not localize to mitochondria. Further analysis suggested that the Alu sequence of BCL-RAMBO-beta might contribute to its proapoptotic ability.
By mutation analysis, Kim et al. (2012) showed that the transmembrane domain of human BCL-RAMBO was essential for mitochondrial targeting, and that mitochondrial localization was crucial for BCL-RAMBO proapoptotic activity. BCL-RAMBO induced loss of mitochondrial membrane potential, thereby promoting mitochondrial permeability transition through a bonkrekic acid-sensitive pathway. BCL-RAMBO interacted directly with adenine nucleotide translocator (SLC25A4; 103220), a component of the mitochondrial permeability transition pore, and suppressed its ADT/ATP-dependent translocation activity, resulting in permeability transition of mitochondria.
By quantitative RT-PCR, Western blot, and immunohistochemical analyses, Jensen et al. (2014) found that BCL2L13 was overexpressed in human glioblastoma and other malignancies. BCL2L13 blocked apoptosis induced by conventional and targeted therapies in cancer by limiting BAX (600040) activation, mitochondrial membrane permeabilization, and subsequent cytochrome c (123970)-driven caspase activation. BCL2L13 interacted with CERS2 (606920) and CERS6 (615336) via its BHNo domain and thereby blocked CERS2-CERS6 heterodimerization and CERS6 homodimerization, which inhibited their activities and apoptosis.
Nakazawa et al. (2016) found that expression of human BCL-RAMBO promoted apoptosis via the mitochondrial pathway in Drosophila S2 cells.
Nakazawa et al. (2016) found that ectopic expression of human BCL-RAMBO interfered with proper differentiation of wing and thorax, as well as embryonic development, in Drosophila. Moreover, ectopic expression of human BCL-RAMBO induced a rough-eye phenotype in Drosophila, including reduction in eye size and loss of ommatidia, bristles, and pigmentation, through activation of effector caspases. Coexpression of baculovirus p35 and Drosophila Diap1 and Diap2 partly rescued the rough-eye phenotype in Drosophila. Further analysis showed that the primary effect of BCL-RAMBO appeared to be induction of apoptosis, with defects in differentiation of cone cells and pigment cells being secondary effects during later stages of eye development. Human BCL-RAMBO interacted genetically with Drosophila orthologs of adenine nucleotide translocators and autophagy-related protein-8 (see 605125).
Jensen, S. A., Calvert, A. E., Volpert, G., Kouri, F. M., Hurley, L. A., Luciano, J. P., Wu, Y., Chalastanis, A., Futerman, A. H., Stegh, A. H. Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc. Nat. Acad. Sci. 111: 5682-5687, 2014. [PubMed: 24706805] [Full Text: https://doi.org/10.1073/pnas.1316700111]
Kataoka, T., Holler, N., Micheau, O., Martinon, F., Tinel, A., Hofmann, K., Tschopp, J. Bcl-rambo, a novel Bcl-2 homologue, that induces apoptosis via its unique C-terminal extension. J. Biol. Chem. 276: 19548-19554, 2001. [PubMed: 11262395] [Full Text: https://doi.org/10.1074/jbc.M010520200]
Kim, J.-Y., So, K.-J., Lee, S., Park, J.-H. Bcl-rambo induces apoptosis via interaction with the adenine nucleotide translocator. FEBS Lett. 586: 3142-3149, 2012. [PubMed: 22921587] [Full Text: https://doi.org/10.1016/j.febslet.2012.08.015]
Nakazawa, M., Matsubara, H., Matsushita, Y., Watanabe, M., Vo, N., Yoshida, H., Yamaguchi, M., Kataoka, T. The human Bcl-2 family member Bcl-rambo localizes to mitochondria and induces apoptosis and morphological aberrations in Drosophila. PLoS One 11: e0157823, 2016. [PubMed: 27348811] [Full Text: https://doi.org/10.1371/journal.pone.0157823]
Yi, P., Zhang, W., Zhai, Z., Miao, L., Wang, Y., Wu, M. Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death. FEBS Lett. 534: 61-68, 2003. [PubMed: 12527362] [Full Text: https://doi.org/10.1016/s0014-5793(02)03778-x]