BCL9

Last updated
BCL9
Protein BCL9 PDB 2gl7.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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

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

Contents

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 Research Articles

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The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Adenomatous polyposis coli</span> Protein-coding gene in the species Homo sapiens

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in Homo sapiens

Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

<span class="mw-page-title-main">TCF7L2</span> Protein-coding gene in humans

Transcription factor 7-like 2 , also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons. As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.

<span class="mw-page-title-main">Lymphoid enhancer-binding factor 1</span> Protein-coding gene in the species Homo sapiens

Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. It is a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.

<span class="mw-page-title-main">BCL3</span> Protein-coding gene in the species Homo sapiens

B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the BCL3 gene.

<span class="mw-page-title-main">Frizzled-6</span> Protein-coding gene in the species Homo sapiens

Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.

<span class="mw-page-title-main">Secreted frizzled-related protein 1</span> Protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

<span class="mw-page-title-main">AXIN2</span> Protein-coding gene in the species Homo sapiens

Axin-2, also known as axin-like protein (Axil), axis inhibition protein 2 (AXIN2), or conductin, is a protein that in humans is encoded by the AXIN2 gene.

<span class="mw-page-title-main">NLK</span> Mammalian protein found in Homo sapiens

Serine/threonine protein kinase NLK is an enzyme that in humans is encoded by the NLK gene. Its name is an abbreviation for Nemo-Like Kinase, Nemo (nmo) being the Drosophila ortholog of the mammalian NLK gene. This enzyme is a member of the Mitogen-activated protein kinase (MAPK) family, although not explicitly designated as such. It is a highly divergent, atypical member of the MAPK group, lacking most features so characteristic of most mitogen-activated protein kinases. Its activation mechanism and downstream targets are still not well characterized.

<span class="mw-page-title-main">PTPRU</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase PCP-2, is an enzyme that in humans is encoded by the PTPRU gene.

<span class="mw-page-title-main">WIF1</span> Protein-coding gene in the species Homo sapiens

Wnt inhibitory factor 1 is a protein that in humans is encoded by the WIF1 gene. WIF1 is a lipid-binding protein that binds to Wnt proteins and prevents them from triggering signalling.

<span class="mw-page-title-main">Protein chibby homolog 1</span> Protein-coding gene in the species Homo sapiens

Protein chibby homolog 1 is a protein that in humans is encoded by the CBY1 gene.

<span class="mw-page-title-main">PYGO2</span> Protein-coding gene in the species Homo sapiens

Pygopus homolog 2 is a protein that in humans is encoded by the PYGO2 gene.

<span class="mw-page-title-main">WNT9A</span> Protein-coding gene in the species Homo sapiens

Protein Wnt-9a is a protein that in humans is encoded by the WNT9A gene.

<span class="mw-page-title-main">FRAT2</span> Protein-coding gene in the species Homo sapiens

GSK-3-binding protein FRAT2 is a protein that in humans is encoded by the FRAT2 gene.

<span class="mw-page-title-main">CXXC5</span> Protein-coding gene in the species Homo sapiens

CXXC-type zinc finger protein 5 is a protein that is encoded by the CXXC5 gene in humans.

<span class="mw-page-title-main">TCF/LEF family</span> Group of genes

The TCF/LEF family is a group of genes that encode transcription factors which bind to DNA through a SOX-like high mobility group domain. They are involved in the Wnt signaling pathway, particularly during embryonic and stem-cell development, but also had been found to play a role in cancer and diabetes. TCF/LEF factors recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors.

<span class="mw-page-title-main">BCL9L</span> Protein-coding gene in the species Homo sapiens

B-cell CLL/lymphoma 9 like is a protein that in humans is encoded by the BCL9L gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000116128 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "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