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MAGEA3 (melanoma antigen family A, 3)

Written2014-04Biswajit Das, Sujit Suklabaidya, Sumeet Jain, Manas R Baisakh, Shantibhusan Senapati
Institute of Life Sciences, Bhubaneswar, Odisha 751023, India (BD, SSu, SJ, SSe); Apollo Hospital, Bhubaneswar, Odisha 751003, India (MRB)

Abstract In the year 1991 Van der Bruggen P et al. cloned and named MAGE-1 gene that encodes MZ2E antigen, which is expressed in melanoma tissues and cell lines (van der Bruggen et al., 1991). Since then based on sequence similarity MAGE family has expanded to more than 60 genes (Chomez et al., 2001). According to their chromosomal location and tissue-specific expression pattern, all the members of this family are categorized into two groups; type I (cancer and testis specific) and type II (ubiquitous) MAGE. MAGEA sub-family has 12 members starting from MAGEA1 to MAGEA12, among them MAGEA7 is a pseudo-gene (Doyle et al., 2010). The current review summarizes the information specifically on MAGEA3's DNA/RNA, protein structure, function and where the gene is implicated.

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Alias (NCBI)CT1.3
HGNC Alias symbHYPD
HGNC Alias namemelanoma-associated antigen 3
 antigen MZ2-D
 MAGE-3 antigen
 cancer/testis antigen family 1, member 3
HGNC Previous nameMAGE3
HGNC Previous namemelanoma antigen family A3
LocusID (NCBI) 4102
Atlas_Id 41247
Location Xq28  [Link to chromosome band Xq28]
Location_base_pair Starts at 152698794 and ends at 152702347 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping MAGEA3.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note MAGEA3 is the third member of MAGEA CT-antigen family. Due to its restricted expression in normal testicular and placental trophoblast cells and aberrant expression in various types of cancer cells, MAGEA3 has drawn paramount attention as an anti-cancer immunotherapy.


Description In human X chromosome; MAGEA3, is clustered in q28 along with other MAGEA sub-family members. The gene consists of three exons and is distributed over 3588 bp (Figure 1).
Transcription MAGEA3 gets transcribed from the reverse (minus/negative) strand of the DNA. The transcript or m-RNA harbors three exons, but only the 3rd exon contributes to the whole ORF (Figure 1). Three transcript variants have been reported till date.


  Figure 1. Genomic organization and protein domain structure of MAGEA3.
Description The MAGEA3 protein consists of 314 amino acids. The protein has a molecular weight of 34747 Da and pI 4.57. Like other MAGEA family members, it has a conserved MAGE homology domain (MHD; 116 aa - 286 aa) (Sang et al., 2011). Unfortunately, till date no clear functional role has been identified for this domain. The protein has also one MAGE NH2-terminal and one MAGE COOH-terminal region in its structure (Figure 1). The MAGEA3 protein is 85% and 95% identical to MAGEA2 and MAGEA6, respectively (Atanackovic et al., 2010).
Expression The expression of MAGEA3 is restricted to germ cells of testis (primary spermatocytes and spermatogonia) and placental trophoblast, but no other somatic cellular expression have been reported except in wide variety of tumor cells.
Localisation Cytoplasmic and nuclear expression has been reported (Atanackovic et al., 2010; Barker and Salehi, 2002; Guo et al., 2013).
Function Since the MAGA3 protein is restricted to germ cell of testis and trophoblast of placenta which are immune privileged tissues, the protein is highly immunogenic and recognized by CTLs when expressed elsewhere. Its role in spermatogenesis and embryo development is still unknown. A report says MAGEA3 has the ability to repress p53 function/transactivation, and MAGEA3 knockdown results in increased accumulation of p53 target genes in response to DNA damage (Monte et al., 2006). Moreover, MAGEA3 directly interacts with and enhances the ubiquitin ligase activity of TRIM28 (a RING E3 ubiquitin ligase) and has a probable role in p53 degradation (Doyle et al., 2010). Its other functional implications in various cancer cells are mentioned in this report. MAGEA family members have significant protein sequence identity, which suggests a functional similarity among them. However, a distinct variability in the regulatory regions of MAGEA genes suggests a possible molecular mechanism of carrying out the same function by different members, under different transcription control.

Till now demethylation of promoter region has been reported as the major regulatory mechanism that leads to unusual derepression of MAGEA3 in cancer cells (Figure 2). Histone acetylation is also reported to regulate the expression of MAGEA3 in cancer cells (Kim et al., 2006b; Wischnewski et al., 2006).The MAGEA3 promoter is found to be hypermethylated in response to FGFR2-IIIb and/or FGF7 stimulating signals resulting into MAGEA3 silencing in MAGEA3-positive thyroid cancer cell lines (Kondo et al., 2007). MBD1, a methyl-CpG Binding Domain protein is reported to have the ability to bind the unmethylated promoter of MAGEA3 and suppresses the promoter activity that cannot be retracted by Ets-1 transcription factor (Wischnewski et al., 2007).

  Figure 2. Role of MAGEA3-promoter methylation in spatiotemporal regulation of MAGEA3 gene expression.
Homology Around eight different organisms have orthologs with human MAGEA3.

Implicated in

Entity Various cancers
Note MAGEA3 expression is being reported in colorectal cancer, breast cancer (10%), bladder cancer (37%), pancreatic cancer (40%), multiple myeloma (41%), gastric cancer (48%), glioma (51.3%), melanoma (65%), thyroid cancer (65%) and NSCLC (85%). Information about MAGEA3 expression and significance in various malignancies is mentioned below.
Entity Pancreatic ductal adenocarcinoma
Note MAGEA3 expression has been reported in pancreatic cancer cell lines and tissues. Its expression significantly correlates with poor prognosis in pancreatic cancer patients (Cogdill et al., 2012; Kim et al., 2006a; Kubuschok et al., 2004).
Entity Colorectal cancer
Note Colorectal cancer cell lines express MAGEA3 and its expression in tumor tissue samples significantly correlates with tumor size (Kim et al., 2006b; Shantha Kumara et al., 2012).
Entity Multiple myeloma
Note MAGEA3 expression has been detected in multiple myeloma cell lines and patients samples. Its expression correlates with disease progression i.e. the frequency of expression is higher in relapsed patients than newly diagnosed individuals. Further, silencing of MAGEA3 induced intrinsic apoptosis pathway in proliferating multiple myeloma cells, which indicates the functional role of MAGEA3 in inhibiting apoptosis of cancer cells (Atanackovic et al., 2010; Nardiello et al., 2011).
Entity Thyroid carcinoma
Note MAGEA3 expression has been detected in patient tissue samples and its expression was high in the small papillary carcinoma. Experimental evidences suggest a possible functional role of MAGEA3 in thyroid carcinoma cells' growth, invasion and metastasis (Liu et al., 2008).
Entity Breast cancer
Note MAGEA3 mRNA expression has been reported in breast cancer patient tissue samples. Detection of MAGEA3 mRNA in the sentinel lymph nodes (SLN) of breast cancer patients indicates a high chance of micro-metastasis. It is mostly expressed in the intermediate or poorly differentiated primary breast carcinoma, which is associated with poor prognosis and contributes to higher recurrence rate (Otte et al., 2001; Wascher et al., 2001).
Entity Lung cancer (NSCLC)
Note MAGEA3 mRNA expression has been reported in lung cancer patient tissue samples. High level of MAGEA3 is a potential marker for poor prognosis in NSCLC patients (Gure et al., 2005).
Entity Non-Hodgkins lymphoma
Note MAGEA3 expression has been detected both in cell lines and tissue samples (at RNA level). MAGEA3 in peripheral blood of patients can be a potential tumor marker and is a therapeutic target (Han et al., 2010).
Entity Leukemia
Note High level of MAGEA3 expression significantly correlates with higher bone marrow blast (Martínez et al., 2007).
Entity Glioma
Note MAGE3 protein has been detected in glioma tissue samples. Its expression level does not reflect significant difference in overall survival of patients between the pathological grades (Guo et al., 2013).
Entity Gastric cancer
Note Gastric cancer cell lines express MAGEA3; however, no functional data has been reported till date (Honda et al., 2004).


Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells.
Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens T, Meyer S, Kobold S, Bartels K, Pabst C, Lajmi N, Gordic M, Stahl T, Zander AR, Bokemeyer C, Kroger N.
Haematologica. 2010 May;95(5):785-93. doi: 10.3324/haematol.2009.014464. Epub 2009 Dec 16.
PMID 20015885
The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease.
Barker PA, Salehi A.
J Neurosci Res. 2002 Mar 15;67(6):705-12. (REVIEW)
PMID 11891783
An overview of the MAGE gene family with the identification of all human members of the family.
Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S.
Cancer Res. 2001 Jul 15;61(14):5544-51.
PMID 11454705
Targeting the MAGE A3 antigen in pancreatic cancer.
Cogdill AP, Frederick DT, Cooper ZA, Garber HR, Ferrone CR, Fiedler A, Rosenberg L, Thayer SP, Warshaw AL, Wargo JA.
Surgery. 2012 Sep;152(3 Suppl 1):S13-8. doi: 10.1016/j.surg.2012.05.031. Epub 2012 Jul 6.
PMID 22770803
MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases.
Doyle JM, Gao J, Wang J, Yang M, Potts PR.
Mol Cell. 2010 Sep 24;39(6):963-74. doi: 10.1016/j.molcel.2010.08.029.
PMID 20864041
The expression and clinical significance of melanoma-associated antigen-A1, -A3 and -A11 in glioma.
Guo L, Sang M, Liu Q, Fan X, Zhang X, Shan B.
Oncol Lett. 2013 Jul;6(1):55-62. Epub 2013 May 15.
PMID 23946777
Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer.
Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA, Gnjatic S, Ritter G, Simpson AJ, Chen YT, Old LJ, Altorki NK.
Clin Cancer Res. 2005 Nov 15;11(22):8055-62.
PMID 16299236
Detection of circulating lymphoma cells in patients with non-Hodgkin lymphoma using MAGE-A3 gene expression in peripheral blood.
Han MH, Eom HS, Park WS, Yun T, Park S, Kim HJ, Jeon CH, Kong SY.
Leuk Res. 2010 Sep;34(9):1127-31. doi: 10.1016/j.leukres.2009.11.028. Epub 2009 Dec 29.
PMID 20036422
Demethylation of MAGE promoters during gastric cancer progression.
Honda T, Tamura G, Waki T, Kawata S, Terashima M, Nishizuka S, Motoyama T.
Br J Cancer. 2004 Feb 23;90(4):838-43.
PMID 14970862
The clinical significance of MAGEA3 expression in pancreatic cancer.
Kim J, Reber HA, Hines OJ, Kazanjian KK, Tran A, Ye X, Amersi FF, Martinez SR, Dry SM, Bilchik AJ, Hoon DS.
Int J Cancer. 2006b May 1;118(9):2269-75.
PMID 16331618
Promoter hypomethylation and reactivation of MAGE-A1 and MAGE-A3 genes in colorectal cancer cell lines and cancer tissues.
Kim KH, Choi JS, Kim IJ, Ku JL, Park JG.
World J Gastroenterol. 2006a Sep 21;12(35):5651-7.
PMID 17007017
The cancer/testis antigen melanoma-associated antigen-A3/A6 is a novel target of fibroblast growth factor receptor 2-IIIb through histone H3 modifications in thyroid cancer.
Kondo T, Zhu X, Asa SL, Ezzat S.
Clin Cancer Res. 2007 Aug 15;13(16):4713-20.
PMID 17699848
Expression of cancer testis antigens in pancreatic carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis.
Kubuschok B, Xie X, Jesnowski R, Preuss KD, Romeike BF, Neumann F, Regitz E, Pistorius G, Schilling M, Scheunemann P, Izbicki JR, Lohr JM, Pfreundschuh M.
Int J Cancer. 2004 Apr 20;109(4):568-75.
PMID 14991579
The melanoma-associated antigen A3 mediates fibronectin-controlled cancer progression and metastasis.
Liu W, Cheng S, Asa SL, Ezzat S.
Cancer Res. 2008 Oct 1;68(19):8104-12. doi: 10.1158/0008-5472.CAN-08-2132.
PMID 18829569
mRNA expression of MAGE-A3 gene in leukemia cells.
Martinez A, Olarte I, Mergold MA, Gutierrez M, Rozen E, Collazo J, Amancio-Chassin O, Ordonez RM, Montesinos JJ, Mayani H, McCurdy DK, Ostrosky-Wegman P, Garrido-Guerrero E, Miranda EI.
Leuk Res. 2007 Jan;31(1):33-7. Epub 2006 Jun 27.
PMID 16806467
MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents.
Monte M, Simonatto M, Peche LY, Bublik DR, Gobessi S, Pierotti MA, Rodolfo M, Schneider C.
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11160-5. Epub 2006 Jul 17.
PMID 16847267
MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.
Nardiello T, Jungbluth AA, Mei A, Diliberto M, Huang X, Dabrowski A, Andrade VC, Wasserstrum R, Ely S, Niesvizky R, Pearse R, Coleman M, Jayabalan DS, Bhardwaj N, Old LJ, Chen-Kiang S, Cho HJ.
Clin Cancer Res. 2011 Jul 1;17(13):4309-19. doi: 10.1158/1078-0432.CCR-10-1820. Epub 2011 May 12.
PMID 21565982
MAGE-A gene expression pattern in primary breast cancer.
Otte M, Zafrakas M, Riethdorf L, Pichlmeier U, Loning T, Janicke F, Pantel K.
Cancer Res. 2001 Sep 15;61(18):6682-7.
PMID 11559535
MAGE-A family: attractive targets for cancer immunotherapy.
Sang M, Lian Y, Zhou X, Shan B.
Vaccine. 2011 Nov 3;29(47):8496-500. doi: 10.1016/j.vaccine.2011.09.014. Epub 2011 Sep 18. (REVIEW)
PMID 21933694
MAGE-A3 is highly expressed in a subset of colorectal cancer patients.
Shantha Kumara HM, Grieco MJ, Caballero OL, Su T, Ahmed A, Ritter E, Gnjatic S, Cekic V, Old LJ, Simpson AJ, Cordon-Cardo C, Whelan RL.
Cancer Immun. 2012;12:16. Epub 2012 Dec 28.
PMID 23390371
Detection of MAGE-A3 in breast cancer patients' sentinel lymph nodes.
Wascher RA, Bostick PJ, Huynh KT, Turner R, Qi K, Giuliano AE, Hoon DS.
Br J Cancer. 2001 Nov 2;85(9):1340-6.
PMID 11720472
Methyl-CpG binding domain proteins and their involvement in the regulation of the MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 gene promoters.
Wischnewski F, Friese O, Pantel K, Schwarzenbach H.
Mol Cancer Res. 2007 Jul;5(7):749-59.
PMID 17634428
A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma.
van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T.
Science. 1991 Dec 13;254(5038):1643-7.
PMID 1840703


This paper should be referenced as such :
B Das, S Suklabaidya, S Jain, MR Baisakh, S Senapati
MAGEA3 (melanoma antigen family A, 3)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(1):28-31.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)MAGEA3   6801
Entrez_Gene (NCBI)MAGEA3    MAGE family member A3
AliasesCT1.3; HIP8; HYPD; MAGE3; 
GeneCards (Weizmann)MAGEA3
Ensembl hg19 (Hinxton)ENSG00000221867 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000221867 [Gene_View]  ENSG00000221867 [Sequence]  chrX:152698794-152702347 [Contig_View]  MAGEA3 [Vega]
ICGC DataPortalENSG00000221867
Genatlas (Paris)MAGEA3
SOURCE (Princeton)MAGEA3
Genetics Home Reference (NIH)MAGEA3
Genomic and cartography
GoldenPath hg38 (UCSC)MAGEA3  -     chrX:152698794-152702347 +  Xq28   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MAGEA3  -     Xq28   [Description]    (hg19-Feb_2009)
GoldenPathMAGEA3 - Xq28 [CytoView hg19]  MAGEA3 - Xq28 [CytoView hg38]
Genome Data Viewer NCBIMAGEA3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK223519 AK292384 BC000340 BC005963 BC011744
RefSeq transcript (Entrez)NM_005362
Consensus coding sequences : CCDS (NCBI)MAGEA3
Gene ExpressionMAGEA3 [ NCBI-GEO ]   MAGEA3 [ EBI - ARRAY_EXPRESS ]   MAGEA3 [ SEEK ]   MAGEA3 [ MEM ]
Gene Expression Viewer (FireBrowse)MAGEA3 [ Firebrowse - Broad ]
GenevisibleExpression of MAGEA3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4102
GTEX Portal (Tissue expression)MAGEA3
Human Protein AtlasENSG00000221867-MAGEA3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP43357   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP43357  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP43357
Domaine pattern : Prosite (Expaxy)MAGE (PS50838)   
Domains : Interpro (EBI)MAGE    MAGE_N    MAGE_WH1    MAGE_WH2    MAGEA3/MAGEA6    MHD_dom   
Domain families : Pfam (Sanger)MAGE (PF01454)    MAGE_N (PF12440)   
Domain families : Pfam (NCBI)pfam01454    pfam12440   
Domain families : Smart (EMBL)MAGE (SM01373)  MAGE_N (SM01392)  
Conserved Domain (NCBI)MAGEA3
PDB (RSDB)1QEW    4V0P    5BRZ   
PDB Europe1QEW    4V0P    5BRZ   
PDB (PDBSum)1QEW    4V0P    5BRZ   
PDB (IMB)1QEW    4V0P    5BRZ   
Structural Biology KnowledgeBase1QEW    4V0P    5BRZ   
SCOP (Structural Classification of Proteins)1QEW    4V0P    5BRZ   
CATH (Classification of proteins structures)1QEW    4V0P    5BRZ   
AlphaFold pdb e-kbP43357   
Human Protein Atlas [tissue]ENSG00000221867-MAGEA3 [tissue]
Protein Interaction databases
IntAct (EBI)P43357
Ontologies - Pathways
Ontology : AmiGOprotein binding  endoplasmic reticulum  negative regulation of autophagy  negative regulation of protein processing  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  caspase binding  negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  
Ontology : EGO-EBIprotein binding  endoplasmic reticulum  negative regulation of autophagy  negative regulation of protein processing  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  caspase binding  negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  
NDEx NetworkMAGEA3
Atlas of Cancer Signalling NetworkMAGEA3
Wikipedia pathwaysMAGEA3
Orthology - Evolution
GeneTree (enSembl)ENSG00000221867
Phylogenetic Trees/Animal Genes : TreeFamMAGEA3
Homologs : HomoloGeneMAGEA3
Homology/Alignments : Family Browser (UCSC)MAGEA3
Gene fusions - Rearrangements
Fusion : QuiverMAGEA3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMAGEA3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MAGEA3
Exome Variant ServerMAGEA3
GNOMAD BrowserENSG00000221867
Varsome BrowserMAGEA3
ACMGMAGEA3 variants
Genomic Variants (DGV)MAGEA3 [DGVbeta]
DECIPHERMAGEA3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMAGEA3 
ICGC Data PortalMAGEA3 
TCGA Data PortalMAGEA3 
Broad Tumor PortalMAGEA3
OASIS PortalMAGEA3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMAGEA3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DMAGEA3
Mutations and Diseases : HGMDMAGEA3
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)MAGEA3
DoCM (Curated mutations)MAGEA3
CIViC (Clinical Interpretations of Variants in Cancer)MAGEA3
NCG (London)MAGEA3
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry MAGEA3
NextProtP43357 [Medical]
Target ValidationMAGEA3
Huge Navigator MAGEA3 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDMAGEA3
Pharm GKB GenePA30547
Clinical trialMAGEA3
DataMed IndexMAGEA3
Other databaseCTDatabase
PubMed94 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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