Melanoma Antigen (MAGE) Family - More than a Cancer Cell Marker

The melanoma antigen (MAGE) protein family, containing a ~180-amino-acid MAGE homology domain (MHD), are conserved in eukaryotes and have ~40 members in human and mouse. MAGEA1, the founder member of this family, was first identified as a cancer cell marker in melanoma, and soon after, it was found having restricted expression in male gonad, a mammalian body sites with immune privilege. Due to the antigenic potential, male germline expression, and aberrantly re-activated in cancer cells, two third of MAGE proteins have been categorizes as cancer-testis antigens (CTA).

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Adenocarcinoma of Human colon tissue stained with anti-MAGEA3 mouse monoclonal antibody (TA800828)
Adenocarcinoma of Human colon tissue stained with anti-MAGEA3 mouse monoclonal antibody (TA800828)
Carcinoma of Human bladder tissue stained with anti-MAGEA4 mouse monoclonal antibody (TA505362)
Carcinoma of Human bladder tissue stained with anti-MAGEA4 mouse monoclonal antibody (TA505362)
Carcinoma of Human bladder tissue stained with anti-MAGEB1 mouse monoclonal antibody (TA800473)
Carcinoma of Human bladder tissue stained with anti-MAGEB1 mouse monoclonal antibody (TA800473)
Adenocarcinoma of Human ovary tissue using anti-MAGEB18 mouse monoclonal antibody (TA502633)
Adenocarcinoma of Human ovary tissue using anti-MAGEB18 mouse monoclonal antibody (TA502633)

MAGE Proteins: Normal function and Implication in Diseases

The physiological functions of MAGE proteins are diverse. For example, MAGEAs enhance the resistance to the genotoxic stress during spermatogenesis. MAGEB2 maintains thermo-sensitive spermatogenesis by suppressing stress granule formation. MAGED1 regulates neuronal apoptosis during neurogenesis and plays essential roles in various brain functions, such as depression, memory, behavior, and circadian rhythm. MAGED2, mutations of which cause X-linked polyhydramnios with prematurity and a transient form of antenatal Bartter's syndrome, regulates expression and function of Na-K-Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Children with MAGEG1 mutations suffered from lung disease immunodeficiency and chromosome breakage syndrome. MAGEL2 is implicated in various human genetic disorders, e.g. Prader-Willi syndrome and Schaaf-Yang syndrome.

MAGE Proteins in Cancers

MAGE proteins have widespread expression in different cancers and are usually poor prognostic markers for cancer patients. As convincing cancer cell markers, MAGE proteins (e.g. MAGEA1, A3, A4, A6, A10, A12, C2) have been immuno-targeted in many clinical trials for cancer. However, myriad evidence indicates that MAGE proteins also play an active role in oncogenicity, tumor progression, and cancer cell survival. For example, MAGEA3 can suppresses cancer cell apoptosis through directly interacting with TP53. MAGEA3 can also complex with TRIM28 to ubiquitinate and degrade TP53 or AMPKα, a master sensor/regulator of cell energy homeostasis, which is commonly suppressed in early-stage cancers. MAGEA11 complexed with HUWE1 performs ubiquitin E3 ligase activity to degrade PCF11, a mRNA 3' end processing complex protein, resulting in 3' UTR shortening, a common feature of most cancer cells. MAGEF1-NSMCE1 E3 ubiquitin ligases ubiquitinate and degrade MMS19, an essential protein in cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway, leading to defects in DNA repair and increasing mutation burden in cancer cells. MAGE proteins should be considered as new therapeutic targets for cancers.

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MAGE in Clinical Trial
A1 A3 A4 A6 A10 A12 C2
MAGE - Ubiquitin E3 Ligase
TRIM28 RAD18 HUWE1 SKIP2 LNX1 RBX1 PJA1 NSMCE1 TRIM27 RNF41
MAGE Family
A1 A2 A3 A4 A5 A6 A8 A9 A10 A11 A12 B1 B2 B3 B4 B5 B6 B10 B16 B17 B18 C1 C2 C3 D1 D2 D3 D4 E1 E2 F1 G1 H1 L2 NDN
Gene CTA* Function Associated proteins Activity Target Pathway Reference (PubMed ID)
MAGEA2 x transcription TP53, HDAC3 transcription repressor CDKN1A cell cycle regulation 16847267
transcription chromatin binding blocker TP53 tumor suppression 21056992
protein degradation TRIM28 E3 ubiquitin ligase TP53 tumor suppression 20864041
MAGEA3/6 x protein degradation TRIM28 E3 ubiquitin ligase AMPK alpha (PRKAA1) cell metabolism 25679763
protein degradation TRIM28 E3 ubiquitin ligase ZNF382 cell cycle regulation 21876767
protein degradation TRIM28 E3 ubiquitin ligase FBP1 cell metabolism 28394358
unknown negetive regulator BIRC5 apoptosis 34166362
MAGEA4 x protein degradation RAD18 E3 ubiquitin ligase PCNA Trans-lesion synthesis (TLS) 27377895
MAGEA11 x protein degradation HUWE1 E3 ubiquitin ligase PCF11 mRNA alternative polyadenylation (APA) 31980388
Transcription AR, EP300, NCOA2 transcription activator KLK3 androgen response 20448036
Transcription PGR (B isoform) transcription activator FKBP5 progesteron response 22891251
protein degradation/ stabilization SKP2 (SCF complex) E3 ubiquitin ligase CCNA2, E2F1, RBL1 cell cycle regulation 27720894
MAGEB2 x Translation translation repressor (DDX5 antagonist) G3BP1 stress granule formation 32692974
Transcription HDAC1 transcription activator E2F1 cell cycle regulation 26468294
Transcription rRNA transcription pre-initiation complex UBTF ribosome biogenesis 33741433
MAGEB18 x protein degradation LNX1 E3 ubiquitin ligase unknown 20864041
MAGEC2 x protein degradation TRIM28 E3 ubiquitin ligase AMPK alpha (PRKAA1) cell metabolism 25679763
protein degradation TRIM28 E3 ubiquitin ligase TP53 tumor suppression 20864041
protein degradation TRIM28 E3 ubiquitin ligase ZNF382 cell cycle regulation 21876767
protein degradation ubiquitination ZMYND11 tumor suppression 24866244
protein stabilization polyubiquitination inhibition STAT3 cancer metastasis 27775077
protein stabilization RBX1, Skp1-Cullin1-F box protein (SCF) E3 ubiquitin ligase inhibition CCNE1 cell cycle regulation 26540345
protein degradation TRIM28 E3 ubiquitin ligase FBP1 cell metabolism 28394358
MAGED1 Signaling NGFR signaling adaptor JNK neuronal apoptosis 12376548
Signaling UNC5A signaling adaptor neuronal apoptosis 12598531
protein degradation pro-apoptotic protein XIAP neuronal apoptosis 11546791
protein degradation pro-apoptotic protein AATF neuronal apoptosis 17488777
Signaling TAK1, TAB1, XIAP signaling complex MAPK14 apoptosis 16107717
Transcription transcription coactivator DLX5 cell differentiation 11084035
protein degradation PJA1 E3 ubiquitin ligase unkown 20864041
transcription NDN transcription factor modulator MSX1 cell differentiation 15272023
protein degradation ubiquitination SLC6A4 neurotransmitter serotonin retrieval 22457503
transcription RORA transcription coactivator ARNTL circadian rhythm 20300063
transcription CREB1 transcription coactivator BDNF, ATF4, NRXN1, GRIN2B, EGR1 synaptic plasticity 24700102
MAGED2 unkown NCL unkown cell cycle: G1/S transition 29371029
transcription TP53 transcription factor modulator apoptosis 17912449
protein stablization GNAS, DNAJB1 unkown SLC12A1, SLC12A3 Bartter's syndrome 27120771
MAGEF1 protein degradation NSMCE1 E3 ubiquitin ligase MMS19 cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway 29225034
MAGEG1 (NDNL2, NSMCE3) protein complex SMC5/6 complexes DNA replication fork stabilizer DNA replication and repair 17005570
protein degradation NSMCE1 E3 ubiquitin ligase unknown 20864041
MAGEH1 unkown GADD45G caspases activation apoptosis 34788311
MAGEL2 protein degradation E3 ubiquitin ligase CRY1 circadian rhythm 32315313
mRNA processing mRNA m6A methylation YTHDF2 RNA metabolism 34265304
signaling TRIM27, USP7 E3 ubiquitin ligase WASHC1 endosomal protein recycling 26365382
signaling NDN, RNF41, USP8 E3 ubiquitin ligase LEPR endosomal protein recycling 28973533
NDN transcription SIRT1 deacetylase TP53 neuronal apoptosis 18753379

*Cancer Testis Antigen

References