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MTA3 (metastasis associated 1 family, member 3 )

Written2010-11Ansgar Brüning, Ioannis Mylonas
University Hospital Munich, Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Marchioninistrasse 15, 81377 Munchen, Germany
Updated2014-06Ansgar Brüning, Ioannis Mylonas
University Hospital Munich, Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Marchioninistrasse 15, 81377 Munchen, Germany

Abstract MTA3 functions as a transcriptional repressor through interacting with histone deacetylases and nucleosome remodelling complexes such as Mi-2/NuRD. Since MTA3 inhibits expression of SNAIL, a transcriptional repressor of the cell adhesion protein E-cadherin, downregulation of MTA3 was found to be associated with reduced E-cadherin levels and advanced cancer stages. Recent data also revealed upregulation of MTA3 in non-small lung cancer cells and highly aggressive subtypes of endometrial cancer, additionally indicating cancer-promoting effects of MTA3.

Keywords Metastasis; gene regulation; chromosome remodelling; oestrogen receptor; E-cadherin; B cell development; cell cycle

(Note : for Links provided by Atlas : click)

Identity

Alias_namesmetastasis associated gene family
Alias_symbol (synonym)KIAA1266
Other alias
HGNC (Hugo) MTA3
LocusID (NCBI) 57504
Atlas_Id 41445
Location 2p21  [Link to chromosome band 2p21]
Location_base_pair Starts at 42721709 and ends at 42984087 bp from pter ( according to hg19-Feb_2009)  [Mapping MTA3.png]
Fusion genes
(updated 2016)
MTA3 (2p21) / ABCG8 (2p21)MTA3 (2p21) / KCNMA1 (10q22.3)MTA3 (2p21) / SEC31A (4q21.22)
ZFX (Xp22.11) / MTA3 (2p21)

DNA/RNA

 
  Genomic organization of the human MTA3 gene. The intron/exon structure of MTA3 with start (ATG) and stop (TAA) codons indicated. All 14 exons are depicted; the intron sequences shortened for better graphical visualization.
Description The human MTA3 gene was identified through sequence homologies to other members of the MTA gene family (human MTA1, human MTA2, murine MTA3). The human MTA3 gene is composed of 14 exons. The MTA3 promoter sequence contains SP1, AP1, and oestrogen receptor binding sites (ER half sites).
Transcription Two open reading frames of 1785 bp (isoform 1; 594 aa; MTA3L) and 1548 bp (isoform 2; 515 aa; MTA3S, MTA3) were identified and predicted to be transcribed. The smaller isoform (MTA3S = MTA3) appears to be the most abundantly expressed isoform at the RNA and protein level.
Pseudogene PGO.9606.51655; PGO.9606.72237.

Protein

 
  Domain structure of the MTA3 protein. BAH (bromo-adjacent homology) domain: putative protein-protein interaction domain, involved in gene silencing; ELM (Egl-27 and MTA1 homology) domain: unknown function; SANT (SWI3, ADA2, N-CoR and TFIIIB B) domain: putative DNA binding domain; ZnF (GATA-type zinc finger) domain: direct DNA binding domain.
Description MTA3 functions as a transcriptional repressor by interacting with histone deacetylases and nucleosome remodelling complexes such as Mi-2/NuRD.
Expression MTA3 expression has been found in normal human breast, ovarian, lung, and endometrial epithelial cells, in malignant breast, ovarian, lung, and endometrial cancer cells and cancer cell lines, in trophoblast cells and chorionic cancer cell lines, in germinal centre B cells, and in B cell-derived lymphomas. A tissue distribution analysis of MTA3 expression in mice revealed a widespread distribution of MTA3 in the developing embryo and in adult tissues (heart, brain, spleen, lung, liver and kidney).
Localisation MTA3 exhibits primarily a nuclear localisation, although additional cytoplasmic localisation has been described.
 
  The MTA3 regulation network. A. Breast ductal epithelia cells; epithelial cancer cells. B. Germinal center B lymphocytes; B cell-derived lymphomas.
The regulation of MTA3 expression and its target genes by transcriptional activators (green) and transcriptional repressors (red) is shown. ER: oestrogen receptor.
Function In epithelial cells, MTA3 maintains the expression of E-cadherin through the suppression of the E-cadherin inhibitor SNAIL. Expression of MTA3 is regulated by oestrogens via direct binding of the oestrogen receptor to the MTA3 promoter and is thus involved in the generation and maintenance of oestrogen-dependent epithelia such as the breast ductal epithelium.
Mammary gland development
Animal experiments revealed involvement of MTA3 expression in mammary gland morphogenesis mediated by the suppression of the Wnt4 signalling pathway and upregulation of epithelial cell adhesion proteins such as E-cadherin.
Normal mammary gland development, as confirmed and studied by several knock out and knock in mouse models, relies on the concerted and correct integration of divers signalling pathways, including the Wnt signalling pathway. Secretion of Wnt factors and their binding by mammary epithelial cells is necessary for correct gland development and its deregulation has been described to be involved in tumorigenesis. MTA3 has been shown to inhibit Wnt4 expression by its transcriptional repression function, causing reduced Wnt4 secretion and subsequent lower beta-catenin levels. Therefore, based on the observations made with transgenic mouse models, expression of MTA3 in mammary epithelial cells has been associated with the inhibition of ductal branching in virgin and pregnant murine mammary glands.
Epithelial cancer
Reduced MTA3 expression in epithelial breast cancer, endometrial cancer, and ovarian cancer is associated with cancer progression by promoting the epithelial-mesenchymal transition (EMT). It is principally believed that reduced expression of MTA3 allows higher expression levels of SNAIL and SLUG, two repressors of metastasis-associated cell adhesion proteins such as E-cadherin and occludin. Conversely, MTA3 expression was found to be elevated in non-small lung cancer and in uterine non-endometrioid cancer, in which a growth-promoting effect of MTA3 overexpression was suggested.
Haemangiogenesis and lymphomagenesis
A high expression level of MTA3 was found in germinal centre B lymphocytes, suggesting an involvement in B cell maturation by direct interaction with BCL6. BCL6 (B-cell lymphoma-6) is a transcriptional repressor that is co-expressed with MTA3 in the germinal centre, where normal B cells proliferate and undergo maturation. BCL6 functions as a transcriptional repressor and suppresses, in cooperation with MTA3, the expression of PRDM1 (Pr domain-containing protein 1), a master regulator of plasma cell differentiation. Overexpression of BCL6 is often observed in lymphomas, especially in large B-cell lymphomas. Thus, the cooperative action of BCL6 together with MTA3 is believed to block differentiation of large B-cell lymphomas, facilitating lymphomagenesis.
Placenta development
A conspicuously high expression level of MTA3 in trophoblast cells and trophoblast tumour cells has suggested involvement of MTA3 in placenta development and homeostasis. MTA3 expression was found to be elevated in preeclampsia patients and to negatively interfere with hCG (human chorionic gonadotropin) expression.
Homology MTA3 exhibits a high homology to human MTA1, MTA2, and murine MTA3.

Implicated in

Note
  
Entity Endometrial cancer
Note MTA3 expression is significantly reduced in endometrioid adenocarcinomas of poor differentiation, although not associated with patients' survival. By contrast, in uterine non-endometrioid carcinomas, a highly aggressive subtype of endometrial cancer, MTA3 expression demonstrated a significant association with FIGO surgical stage, lymph node involvement, and lymphovascular space invasion. In uterine non-endometroid cancer, MTA3 was also revealed to be a significant independent prognostic parameter, associated with patients' progression-free survival, cause-specific survival, and overall survival.
  
  
Entity Ovarian cancer
Note MTA3 expression is reduced in ovarian cancer with poor differentiation, although not at significant levels.
  
  
Entity Breast cancer
Note Although extensively studied on breast cancer cells and tissues, revealing a close correlation of MTA3 expression with oestrogen receptor expression, no studies have yet shown a direct association of MTA3 expression with clinicopathological parameters in breast cancer.
  
  
Entity Lung cancer
Note MTA3 was found to be upregulated in NSCLC (non-small cell lung cancer) tissues and its overexpression correlated with lymph node status and poor patients' prognosis.
  
  
Entity Gastric cancer, oesophagal cancer
Note In gastroesophageal junction (GEJ) adenocarcinomas, MTA3 expression was found to be reduced in cancer tissues and reduced MTA3 expression correlated with worse overall patients' survival.
  
  
Entity Ovary (non-malignant)
Note Murine ovarian granulosa cells of all follicular stages were shown to express high levels of MTA3. Expression of MTA3 in granulosa cells was also shown to promote cell cycle progression by controlling entry into the M phase.
  
  
Entity Placenta
Note A high expression level of MTA3 was observed in placental trophoblast cells and chorionic carcinoma cells. In patients with preeclamptic gestational disease, MTA3 expression was found to be downregulated and shown to be involved in human chorionic gonadotropin expression by directly repressing the hCG promoter, leading to dysregulated hCG expression as observed in preeclampsia.
  

Bibliography

The metastasis-associated gene MTA3 is downregulated in advanced endometrioid adenocarcinomas.
Bruning A, Juckstock J, Blankenstein T, Makovitzky J, Kunze S, Mylonas I.
Histol Histopathol. 2010 Nov;25(11):1447-56.
PMID 20865667
 
The metastasis-associated genes MTA1 and MTA3 are abundantly expressed in human placenta and chorionic carcinoma cells.
Bruning A, Makovitzky J, Gingelmaier A, Friese K, Mylonas I.
Histochem Cell Biol. 2009 Jul;132(1):33-8. doi: 10.1007/s00418-009-0595-z. Epub 2009 Apr 12.
PMID 19363681
 
MTA3 regulates CGB5 and Snail genes in trophoblast.
Chen Y, Miyazaki J, Nishizawa H, Kurahashi H, Leach R, Wang K.
Biochem Biophys Res Commun. 2013 Apr 19;433(4):379-84. doi: 10.1016/j.bbrc.2013.02.102. Epub 2013 Mar 17.
PMID 23510993
 
The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma.
Dong H, Guo H, Xie L, Wang G, Zhong X, Khoury T, Tan D, Zhang H.
PLoS One. 2013 May 3;8(5):e62986. doi: 10.1371/journal.pone.0062986. Print 2013.
PMID 23671646
 
MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation.
Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, Boss JM, Wade PA.
Cell. 2004a Oct 1;119(1):75-86.
PMID 15454082
 
Hormonal regulation of metastasis-associated protein 3 transcription in breast cancer cells.
Fujita N, Kajita M, Taysavang P, Wade PA.
Mol Endocrinol. 2004b Dec;18(12):2937-49. Epub 2004 Sep 9.
PMID 15358836
 
The BCL6-associated transcriptional co-repressor, MTA3, is selectively expressed by germinal centre B cells and lymphomas of putative germinal centre derivation.
Jaye DL, Iqbal J, Fujita N, Geigerman CM, Li S, Karanam S, Fu K, Weisenburger DD, Chan WC, Moreno CS, Wade PA.
J Pathol. 2007 Sep;213(1):106-15.
PMID 17573669
 
Metastasis-associated protein 3 (MTA3) regulates G2/M progression in proliferating mouse granulosa cells.
Kwintkiewicz J, Padilla-Banks E, Jefferson WN, Jacobs IM, Wade PA, Williams CJ.
Biol Reprod. 2012 Mar 8;86(3):1-8. doi: 10.1095/biolreprod.111.096032. Print 2012 Mar.
PMID 22075476
 
Overexpression of MTA3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer.
Li H, Sun L, Xu Y, Li Z, Luo W, Tang Z, Qiu X, Wang E.
PLoS One. 2013 Jun 19;8(6):e66679. Print 2013.
PMID 23840517
 
Mta3-NuRD complex is a master regulator for initiation of primitive hematopoiesis in vertebrate embryos.
Li X, Jia S, Wang S, Wang Y, Meng A.
Blood. 2009 Dec 24;114(27):5464-72. doi: 10.1182/blood-2009-06-227777. Epub 2009 Oct 28.
PMID 19864643
 
Genistein inhibits placental choriocarcinoma cell line JAR invasion through ERβ/MTA3/Snail/E-cadherin pathway.
Liu X, Li X, Yin L, Ding J, Jin H, Feng Y.
Oncol Lett. 2011 Sep 1;2(5):891-897. Epub 2011 Jul 5.
PMID 22866146
 
Upstream determinants of estrogen receptor-alpha regulation of metastatic tumor antigen 3 pathway.
Mishra SK, Talukder AH, Gururaj AE, Yang Z, Singh RR, Mahoney MG, Franci C, Vadlamudi RK, Kumar R.
J Biol Chem. 2004 Jul 30;279(31):32709-15. Epub 2004 May 28.
PMID 15169784
 
The metastasis-associated gene MTA3 is an independent prognostic parameter in uterine non-endometrioid carcinomas.
Mylonas I, Bruning A.
Histopathology. 2012 Mar;60(4):665-70. doi: 10.1111/j.1365-2559.2011.04103.x. Epub 2012 Jan 11.
PMID 22235751
 
Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway.
Zhang H, Singh RR, Talukder AH, Kumar R.
Genes Dev. 2006 Nov 1;20(21):2943-8. Epub 2006 Oct 18.
PMID 17050676
 
Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer.
Zhang H, Stephens LC, Kumar R.
Clin Cancer Res. 2006 Mar 1;12(5):1479-86.
PMID 16533771
 
Analysis of MAT3 gene expression in NSCLC.
Zheng S, Du Y, Chu H, Chen X, Li P, Wang Y, Ma Y, Wang H, Zang W, Zhang G, Zhao G.
Diagn Pathol. 2013 Oct 9;8:166. doi: 10.1186/1746-1596-8-166.
PMID 24107548
 

Citation

This paper should be referenced as such :
A Brè_ning, I Mylonas
MTA3 (metastasis associated 1 family, member 3 )
Atlas Genet Cytogenet Oncol Haematol. 2015;19(2):137-140.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MTA3ID41445ch2p21.html
History of this paper:
Bröning, A ; Mylonas, I. MTA3 (metastasis associated 1 family, member 3). Atlas Genet Cytogenet Oncol Haematol. 2011;15(7):567-569.
http://documents.irevues.inist.fr/bitstream/handle/2042/45996/11-2010-MTA3ID41445ch2p21.pdf


External links

Nomenclature
HGNC (Hugo)MTA3   23784
Cards
AtlasMTA3ID41445ch2p21
Entrez_Gene (NCBI)MTA3  57504  metastasis associated 1 family member 3
Aliases
GeneCards (Weizmann)MTA3
Ensembl hg19 (Hinxton)ENSG00000057935 [Gene_View]  chr2:42721709-42984087 [Contig_View]  MTA3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000057935 [Gene_View]  chr2:42721709-42984087 [Contig_View]  MTA3 [Vega]
ICGC DataPortalENSG00000057935
TCGA cBioPortalMTA3
AceView (NCBI)MTA3
Genatlas (Paris)MTA3
WikiGenes57504
SOURCE (Princeton)MTA3
Genetics Home Reference (NIH)MTA3
Genomic and cartography
GoldenPath hg19 (UCSC)MTA3  -     chr2:42721709-42984087 +  2p22.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MTA3  -     2p22.1   [Description]    (hg38-Dec_2013)
EnsemblMTA3 - 2p22.1 [CytoView hg19]  MTA3 - 2p22.1 [CytoView hg38]
Mapping of homologs : NCBIMTA3 [Mapview hg19]  MTA3 [Mapview hg38]
OMIM609050   
Gene and transcription
Genbank (Entrez)AB033092 AF086450 AK027304 AK122690 AK127245
RefSeq transcript (Entrez)NM_001282755 NM_001282756 NM_020744
RefSeq genomic (Entrez)NC_000002 NC_018913 NT_022184 NW_004929300
Consensus coding sequences : CCDS (NCBI)MTA3
Cluster EST : UnigeneHs.745162 [ NCBI ]
CGAP (NCI)Hs.745162
Alternative Splicing GalleryENSG00000057935
Gene ExpressionMTA3 [ NCBI-GEO ]   MTA3 [ EBI - ARRAY_EXPRESS ]   MTA3 [ SEEK ]   MTA3 [ MEM ]
Gene Expression Viewer (FireBrowse)MTA3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57504
GTEX Portal (Tissue expression)MTA3
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9BTC8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9BTC8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9BTC8
Splice isoforms : SwissVarQ9BTC8
PhosPhoSitePlusQ9BTC8
Domaine pattern : Prosite (Expaxy)BAH (PS51038)    ELM2 (PS51156)    SANT (PS51293)   
Domains : Interpro (EBI)BAH_dom    ELM2_dom    Homeodomain-like    SANT/Myb    SANT_dom    Znf_GATA   
Domain families : Pfam (Sanger)BAH (PF01426)    ELM2 (PF01448)    GATA (PF00320)   
Domain families : Pfam (NCBI)pfam01426    pfam01448    pfam00320   
Domain families : Smart (EMBL)BAH (SM00439)  SANT (SM00717)  ZnF_GATA (SM00401)  
Conserved Domain (NCBI)MTA3
DMDM Disease mutations57504
Blocks (Seattle)MTA3
SuperfamilyQ9BTC8
Human Protein AtlasENSG00000057935
Peptide AtlasQ9BTC8
HPRD12359
IPIIPI00165357   IPI00220288   IPI00880118   IPI00879783   IPI00877659   IPI00877838   IPI00877686   IPI00917955   
Protein Interaction databases
DIP (DOE-UCLA)Q9BTC8
IntAct (EBI)Q9BTC8
FunCoupENSG00000057935
BioGRIDMTA3
STRING (EMBL)MTA3
ZODIACMTA3
Ontologies - Pathways
QuickGOQ9BTC8
Ontology : AmiGOchromatin binding  transcription factor activity, sequence-specific DNA binding  histone deacetylase activity  protein binding  nucleus  nucleoplasm  zinc ion binding  histone deacetylation  intracellular membrane-bounded organelle  sequence-specific DNA binding  negative regulation of transcription, DNA-templated  
Ontology : EGO-EBIchromatin binding  transcription factor activity, sequence-specific DNA binding  histone deacetylase activity  protein binding  nucleus  nucleoplasm  zinc ion binding  histone deacetylation  intracellular membrane-bounded organelle  sequence-specific DNA binding  negative regulation of transcription, DNA-templated  
Pathways : BIOCARTADownregulated of MTA-3 in ER-negative Breast Tumors [Genes]   
REACTOMEQ9BTC8 [protein]
REACTOME Pathways3214815 [pathway]   427389 [pathway]   73762 [pathway]   
NDEx NetworkMTA3
Atlas of Cancer Signalling NetworkMTA3
Wikipedia pathwaysMTA3
Orthology - Evolution
OrthoDB57504
GeneTree (enSembl)ENSG00000057935
Phylogenetic Trees/Animal Genes : TreeFamMTA3
HOVERGENQ9BTC8
HOGENOMQ9BTC8
Homologs : HomoloGeneMTA3
Homology/Alignments : Family Browser (UCSC)MTA3
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMTA3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MTA3
dbVarMTA3
ClinVarMTA3
1000_GenomesMTA3 
Exome Variant ServerMTA3
ExAC (Exome Aggregation Consortium)MTA3 (select the gene name)
Genetic variants : HAPMAP57504
Genomic Variants (DGV)MTA3 [DGVbeta]
DECIPHER (Syndromes)2:42721709-42984087  ENSG00000057935
CONAN: Copy Number AnalysisMTA3 
Mutations
ICGC Data PortalMTA3 
TCGA Data PortalMTA3 
Broad Tumor PortalMTA3
OASIS PortalMTA3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMTA3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMTA3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MTA3
DgiDB (Drug Gene Interaction Database)MTA3
DoCM (Curated mutations)MTA3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MTA3 (select a term)
intoGenMTA3
NCG5 (London)MTA3
Cancer3DMTA3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609050   
Orphanet
MedgenMTA3
Genetic Testing Registry MTA3
NextProtQ9BTC8 [Medical]
TSGene57504
GENETestsMTA3
Huge Navigator MTA3 [HugePedia]
snp3D : Map Gene to Disease57504
BioCentury BCIQMTA3
ClinGenMTA3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD57504
Chemical/Pharm GKB GenePA134953540
Clinical trialMTA3
Miscellaneous
canSAR (ICR)MTA3 (select the gene name)
Probes
Litterature
PubMed49 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMTA3
EVEXMTA3
GoPubMedMTA3
iHOPMTA3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:35:46 CEST 2017

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