BCL2L13

BCL2L13
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2IPD
Identifiers
Aliases	BCL2L13 , BCL-RAMBO, Bcl2-L-13, MIL1, BCL2 like 13
External IDs	MGI: 2136959; HomoloGene: 9111; GeneCards: BCL2L13; OMA:BCL2L13 - orthologs
Gene location (Human) Chr. Chromosome 22 (human) [1] Band 22q11.21 Start 17,628,855 bp [1] End 17,730,855 bp [1]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [2] Band 6 F1|6 57.01 cM Start 120,813,173 bp [2] End 120,869,803 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte gastrocnemius muscle middle temporal gyrus muscle of thigh glutes Skeletal muscle tissue of rectus abdominis islet of Langerhans Brodmann area 23 tibialis anterior muscle deltoid muscle Top expressed in corneal stroma lens muscle of thigh plantaris muscle epithelium of lens soleus muscle digastric muscle triceps brachii muscle yolk sac extensor digitorum longus muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cysteine-type endopeptidase activator activity involved in apoptotic process protein binding Cellular component integral component of membrane mitochondrial membranes nucleus membrane mitochondrion Biological process regulation of apoptotic process activation of cysteine-type endopeptidase activity involved in apoptotic process apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23786 94044 Ensembl ENSG00000099968 ENSMUSG00000009112 UniProt Q9BXK5 P59017 RefSeq (mRNA) NM_001270726 NM_001270727 NM_001270728 NM_001270729 NM_001270730 NM_001270731 NM_001270732 NM_001270733 NM_001270734 NM_001270735 NM_015367 NM_001363824 NM_153516 RefSeq (protein) NP_001257655 NP_001257656 NP_001257657 NP_001257658 NP_001257659 NP_001257660 NP_001257661 NP_001257662 NP_001257663 NP_001257664 NP_056182 NP_001350753 NP_705736 Location (UCSC) Chr 22: 17.63 – 17.73 Mb Chr 6: 120.81 – 120.87 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

BCL2-like 13 (apoptosis facilitator), also known as BCL2L13 or Bcl-rambo, is a protein which in humans is encoded by the BCL2L13 gene on chromosome 22. This gene encodes a mitochondrially-localized protein which is classified under the Bcl-2 protein family. Overexpression of the encoded protein results in apoptosis. ^{[5] [6]} As a result, it has been implicated in cancers such as childhood acute lymphoblastic leukemia (ALL) and glioblastoma multiforme (GBM). ^{[7] [8]} Alternatively spliced transcript variants have been observed for this gene, such as Bcl-rambo beta. ^{[5] [9]}

Structure

As a member of the Bcl-2 protein family, Bcl-rambo comprises four conserved BH domains and a transmembrane (TM) domain. However, unlike the other members, Bcl-rambo does not require the BH domains for its apoptotic function, relying instead on the mitochondrial localization carried out by the TM domain. In addition to these domains, it has conserved B-cell lymphoma 2 homology motifs, as well as an extension at its c-terminal, termed the BHNo domain, which contains two tandem repeats, RTA and RTB. ^{[5] [9]}

An alternatively-spliced protein variant, called Bcl-rambo beta, is composed of only the BH4 domain, completely lacking the BH domains 1 through 3 due to an in-frame stop codon inserted by an Alu element. Without the TM domain, this variant remains in the cytosol and does not localize to the mitochondria. Nonetheless, it still performs proapoptotic activity, mediated by the encoded Alu element, though the exact mechanisms remain to be elucidated. ^[10]

Function

Bcl-rambo is a member of the Bcl-2 family of proteins that regulate apoptosis. In cells, Bcl-rambo is localized to the mitochondria, and its overexpression induces apoptosis that is blocked by caspase inhibitors, whereas inhibitors controlling upstream events of either the 'death receptor' (FLIP, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect. ^[6] Bcl-rambo mediates apoptosis by associating with adenine nucleotide translocator (ANT), a component of the mitochondrial permeability transition pore, to induce its opening. ANT will also facilitate the transfer of ADP and ATP between the cytosol and the matrix. ^[9]

Clinical significance

The BCL2L13 gene has been implicated in a wide spectrum of cancers. Previous clinical studies observed in ALL patients that high expression of BCL2L13 correlated to lower event-free and overall survival. Though statistically significant, the observations contradict the accepted pro-apoptotic function of BCL2L13’s gene product, which should have contributed to cancer cell death and, thus, more favorable survival outcomes. Two possible explanations propose that either 1) Bcl-rambo performs a different biological role in childhood, or 2) alternative splicing could have generated an anti-apoptotic variant. More research is necessary to resolve this discrepancy. ^[7] In another type of cancer, GBM, Bcl-rambo is known to inhibit induced apoptosis in GBM cells by binding two other pro-apoptotic proteins, ceramide synthases 2 (CerS2) and 6 (CerS6), thereby blocking CerS2/6 complex formation and activity. Thus, inhibiting BCL2L13 during cancer treatments may improve survival outcomes. ^[8]

Interactions

BCL2L13 has been shown to interact with:

• CerS2 ^[8] and
• CerS6. ^[8]

References

1. GRCh38: Ensembl release 89: ENSG00000099968 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000009112 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: BCL2L13 BCL2-like 13 (apoptosis facilitator)".
6. Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K, Tschopp J (Jun 2001). "Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension". The Journal of Biological Chemistry. 276 (22): 19548–54. doi: 10.1074/jbc.M010520200 . PMID   11262395.
7. Yang YL, Lin SR, Chen JS, Lin SW, Yu SL, Chen HY, Yen CT, Lin CY, Lin JF, Lin KH, Jou ST, Hu CY, Chang SK, Lu MY, Chang HH, Chang WH, Lin KS, Lin DT (Jan 2010). "Expression and prognostic significance of the apoptotic genes BCL2L13, Livin, and CASP8AP2 in childhood acute lymphoblastic leukemia" (PDF). Leukemia Research. 34 (1): 18–23. doi:10.1016/j.leukres.2009.07.023. PMID   20109966.
8. Jensen SA, Calvert AE, Volpert G, Kouri FM, Hurley LA, Luciano JP, Wu Y, Chalastanis A, Futerman AH, Stegh AH (Apr 2014). "Bcl2L13 is a ceramide synthase inhibitor in glioblastoma". Proceedings of the National Academy of Sciences of the United States of America. 111 (15): 5682–7. Bibcode:2014PNAS..111.5682J. doi: 10.1073/pnas.1316700111 . PMC   3992626 . PMID   24706805.
9. Kim JY, So KJ, Lee S, Park JH (Sep 2012). "Bcl-rambo induces apoptosis via interaction with the adenine nucleotide translocator". FEBS Letters. 586 (19): 3142–9. doi: 10.1016/j.febslet.2012.08.015 . PMID   22921587. S2CID   31709574.
10. • Yi P, Zhang W, Zhai Z, Miao L, Wang Y, Wu M (Jan 2003). "Bcl-rambo beta, a special splicing variant with an insertion of an Alu-like cassette, promotes etoposide- and Taxol-induced cell death". FEBS Letters. 534 (1–3): 61–8. doi: 10.1016/S0014-5793(02)03778-X . PMID   12527362. S2CID   7018829.

External links

• Human BCL2L13 genome location and BCL2L13 gene details page in the UCSC Genome Browser .

Further reading

• Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP (Dec 1999). "The DNA sequence of human chromosome 22". Nature. 402 (6761): 489–95. Bibcode:1999Natur.402..489D. doi: 10.1038/990031 . PMID   10591208.
• Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K, Tschopp J (Jun 2001). "Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension". The Journal of Biological Chemistry. 276 (22): 19548–54. doi: 10.1074/jbc.M010520200 . PMID   11262395.
• Footz TK, Brinkman-Mills P, Banting GS, Maier SA, Riazi MA, Bridgland L, Hu S, Birren B, Minoshima S, Shimizu N, Pan H, Nguyen T, Fang F, Fu Y, Ray L, Wu H, Shaull S, Phan S, Yao Z, Chen F, Huan A, Hu P, Wang Q, Loh P, Qi S, Roe BA, McDermid HE (Jun 2001). "Analysis of the cat eye syndrome critical region in humans and the region of conserved synteny in mice: a search for candidate genes at or near the human chromosome 22 pericentromere". Genome Research. 11 (6): 1053–70. doi:10.1101/gr.154901. PMC   311098 . PMID   11381032.
• Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I (2005). "A genome annotation-driven approach to cloning the human ORFeome". Genome Biology. 5 (10): R84. doi: 10.1186/gb-2004-5-10-r84 . PMC   545604 . PMID   15461802.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (Nov 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi: 10.1016/j.cell.2006.09.026 . PMID   17081983. S2CID   7827573.
• Banga S, Gao P, Shen X, Fiscus V, Zong WX, Chen L, Luo ZQ (Mar 2007). "Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family". Proceedings of the National Academy of Sciences of the United States of America. 104 (12): 5121–6. Bibcode:2007PNAS..104.5121B. doi: 10.1073/pnas.0611030104 . PMC   1829273 . PMID   17360363.