BCL9

B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.^[5][6]

BCL9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2GL7, 2VP7, 2VPB, 2VPD, 2VPE, 2VPG, 3SL9
Identifiers
Aliases	BCL9, LGS, B-cell CLL/lymphoma 9, B cell CLL/lymphoma 9, transcription coactivator, BCL9 transcription coactivator
External IDs	OMIM: 602597; MGI: 1924828; HomoloGene: 3191; GeneCards: BCL9; OMA:BCL9 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.2 Start 147,541,501 bp[1] End 147,626,216 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F2.1 Start 97,110,978 bp[2] End 97,205,233 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence ventricular zone islet of Langerhans right uterine tube smooth muscle tissue left uterine tube body of uterus cerebellar cortex cerebellar hemisphere cardia Top expressed in genital tubercle tail of embryo zygote Rostral migratory stream ventricular zone neural layer of retina ganglionic eminence secondary oocyte neural tube Paneth cell More reference expression data BioGPS More reference expression data
Gene ontology Molecular function beta-catenin binding protein binding transcription coactivator activity Cellular component cytoplasm cis-Golgi network Golgi apparatus nucleus nucleoplasm beta-catenin-TCF complex Biological process skeletal muscle cell differentiation canonical Wnt signaling pathway Wnt signaling pathway somatic stem cell population maintenance myotube differentiation involved in skeletal muscle regeneration positive regulation of transcription by RNA polymerase II regulation of transforming growth factor beta receptor signaling pathway beta-catenin-TCF complex assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 607 77578 Ensembl ENSG00000116128 ENSMUSG00000038256 UniProt O00512 Q9D219 RefSeq (mRNA) NM_004326 NM_029933 RefSeq (protein) NP_004317 NP_084209 Location (UCSC) Chr 1: 147.54 – 147.63 Mb Chr 3: 97.11 – 97.21 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

BCL9, together with its paralogue gene BCL9L (BCL9 like or BCL9.2), have been extensively studied for their role as transcriptional beta-catenin cofactors, fundamental for the transcription of Wnt target genes.^[7]

Recent work, using the mouse (Mus musculus) and zebrafish (Danio rerio) as model organisms, identified an ancient role of BCL9 and BCL9L as key factors required for cardiac development.^[8] This work emphasises the tissue-specific nature of the Wnt/β-catenin mechanism of action, and implicates alterations in BCL9 and BCL9L in human congenital heart defects.

BCL9 and BCL9L have been shown to take part in other tissue-specific molecular mechanisms, showing that their role in the Wnt signaling cascade is only one aspect of their mode of action.^[9]

The conserved homology domain HD1 of BCL9 (and BCL9L) has recently been shown to be interacting with TBX3 in the context of intestinal carcinogenesis; this interaction mediates some tissue-specific signalling functions of the protein.^[10]

Clinical significance

BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies.^[6]

BCL9 and BCL9L are potential clinical targets for human cancers; for instance, the gene expression changes that they promote is associated with a poor outcome in colorectal cancer.^[11]

Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL10, it has clinical significance in lymphoma.

Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder.^[12]

BCL9, together with the paralogue protein BCL9l and PYGO2 also have cytoplasmic functions during tooth development and is particularly important for the formation of enamel. Mice lacking both Pygo1 and Pygo2 or both Bcl9 and Bcl9l develop teeth, a process that requires Wnt/β-catenin transcriptional regulation, but the enamel is structurally disorganized and contains less iron than teeth from control mice. Bcl9, Bcl9l, and Pygo2 are present in the cytoplasm of ameloblasts, the cells that secrete enamel proteins, and colocalize in these cells with amelogenin, the main component of enamel, encoded by the AMELX gene, which has been already implicated as a causative factor of Amelogenesis Imperfecta in humans. Bcl9 interacts with amelogenin and proteins involved in exocytosis and vesicular trafficking, suggesting that these proteins function in the trafficking or secretion of enamel proteins. Therefore, Bcl9, Bcl9l, and Pygo2 have cytoplasmic functions distinct from their roles as transcriptional cofactors downstream of Wnt signaling.^[13] This new discovery might improve our understanding for the treatment of human caries.^[14]

Related gene problems

• 1q21.1 deletion syndrome
• 1q21.1 duplication syndrome

References

1. GRCh38: Ensembl release 89: ENSG00000116128 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038256 – 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. Willis TG, Zalcberg IR, Coignet LJ, Wlodarska I, Stul M, Jadayel DM, et al. (March 1998). "Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21". Blood. 91 (6): 1873–1881. doi:10.1182/blood.V91.6.1873. PMID 9490669.
6. "Entrez Gene: BCL9 B-cell CLL/lymphoma 9".
7. Mosimann C, Hausmann G, Basler K (April 2009). "Beta-catenin hits chromatin: regulation of Wnt target gene activation". Nature Reviews. Molecular Cell Biology. 10 (4): 276–286. doi:10.1038/nrm2654. PMID 19305417. S2CID 7602580.
8. Cantù C, Felker A, Zimmerli D, Prummel KD, Cabello EM, Chiavacci E, et al. (November 2018). "Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling". Genes & Development. 32 (21–22): 1443–1458. doi:10.1101/gad.315531.118. PMC 6217730. PMID 30366904.
9. Cantù C, Zimmerli D, Hausmann G, Valenta T, Moor A, Aguet M, Basler K (September 2014). "Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development". Genes & Development. 28 (17): 1879–1884. doi:10.1101/gad.246140.114. PMC 4197948. PMID 25184676.
10. Zimmerli D, Borrelli C, Jauregi-Miguel A, Söderholm S, Brütsch S, Doumpas N, et al. (August 2020). "TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex". eLife. 9. doi:10.7554/eLife.58123. PMC 7434441. PMID 32808927.
11. Moor AE, Anderle P, Cantù C, Rodriguez P, Wiedemann N, Baruthio F, et al. (December 2015). "BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer". eBioMedicine. 2 (12): 1932–1943. doi:10.1016/j.ebiom.2015.10.030. PMC 4703711. PMID 26844272.
12. Li J, Zhou G, Ji W, Feng G, Zhao Q, Liu J, et al. (March 2011). "Common variants in the BCL9 gene conferring risk of schizophrenia". Archives of General Psychiatry. 68 (3): 232–240. doi:10.1001/archgenpsychiatry.2011.1. PMID 21383261.
13. Cantù C, Pagella P, Shajiei TD, Zimmerli D, Valenta T, Hausmann G, et al. (February 2017). "A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation". Science Signaling. 10 (465): eaah4598. doi:10.1126/scisignal.aah4598. PMID 28174279. S2CID 6845295.
14. "Mutated genes lead to tooth enamel defects that increase risk of caries". News-Medical.net. 2017-02-07. Retrieved 2017-02-08.

Further reading

• Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, et al. (December 1999). "Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations". Leukemia. 13 (12): 1975–1981. doi:10.1038/sj/leu/2401587. PMID 10602418.
• Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, et al. (April 2002). "Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex". Cell. 109 (1): 47–60. doi:10.1016/S0092-8674(02)00679-7. PMID 11955446. S2CID 16720801.
• Knoll A, Dvorák J, Rohrer GA, Cepica S (April 2002). "Linkage and cytogenetic mapping of the BCL9 gene to porcine chromosome 4". Animal Genetics. 33 (2): 162–163. doi:10.1046/j.1365-2052.2002.0831e.x. PMID 12047235.
• Townsley FM, Thompson B, Bienz M (February 2004). "Pygopus residues required for its binding to Legless are critical for transcription and development". The Journal of Biological Chemistry. 279 (7): 5177–5183. doi:10.1074/jbc.M309722200. PMID 14612447.
• Hoffmans R, Basler K (September 2004). "Identification and in vivo role of the Armadillo-Legless interaction". Development. 131 (17): 4393–4400. doi:10.1242/dev.01296. PMID 15294866.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, et al. (August 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–12135. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W (October 2006). "Crystal structure of a beta-catenin/BCL9/Tcf4 complex". Molecular Cell. 24 (2): 293–300. doi:10.1016/j.molcel.2006.09.001. PMID 17052462.
• Hoffmans R, Basler K (January 2007). "BCL9-2 binds Arm/beta-catenin in a Tyr142-independent manner and requires Pygopus for its function in Wg/Wnt signaling". Mechanisms of Development. 124 (1): 59–67. doi:10.1016/j.mod.2006.09.006. PMID 17113272. S2CID 17642255.

External links

• Human BCL9 genome location and BCL9 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: O00512 (B-cell CLL/lymphoma 9 protein) at the PDBe-KB.