MAGEA11 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | MAGEA11 , CT1.11, MAGE-11, MAGE11, MAGEA-11, MAGE family member A11 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 300344; MGI: 1333839; HomoloGene: 121637; GeneCards: MAGEA11; OMA:MAGEA11 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Melanoma-associated antigen 11 is a protein that in humans is encoded by the MAGEA11 gene. [5] [6] It is also involved in the androgen and progesterone receptor signaling pathways.
MAGEA11 is an androgen coregulator specific to primates. [7] It was first identified in human melanomas, and has since been linked to several cancers. [8] It is observed on spermatogonia and primary spermatocytes, and in some prostate and breast cancers. [9]
This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as [dyskeratosis congenita]. Two transcript variants encoding different isoforms have been found for this gene. [6]
MAGEA11 has been shown to interact with TCEA2, [10] androgen receptor [11] [12] and SH2D4A. [10]
MAGE-A genes have several noncoding exons followed by one protein-coding exon. MAGEA11 is mapped to the human chromosome X, forming a locus at q28 with other MAGE-A proteins. MAGE-A11 is located between two copies of MAGEA9 and MAGEA8, and is immediately downstream of the duplicated area. Its sublocus is about 2 Mb from the second sublocus containing the other MAGEA genes. [8]
MAGE-A11 is part of the androgen receptor signaling pathway in humans. It binds directly to the androgen receptor, promoting transcriptional through direct binding to the androgen receptor FXXLF motif region. [7] [13] This control is specific to primates, and is due to a mutation in the androgen receptor from alanine to valine at residue 33, which extends the α-helix, which enables direct MAGE-A11 binding to the androgen receptor. [7] Post-translational modification of the protein by phosphorylation of Thr-360 and monoubiquitinylation of Lys-240 and Lys-245 also stabilizes the interaction with the androgen receptor. [14] MAGE-A11 likely links transcriptionally active androgen receptor dimers. [15] The MAGE-A11 dependent increase in androgen receptor transcriptional activity is mediated by a direct interaction of MAGE-A11 and transcriptional intermediary factor 2 (TIF2), suggesting that MAGE-A11 may act as a bridging factor to recruit other androgen receptor coactivators. [14] Mutations in the androgen receptor that interfere with binding of MAGE-A11 can cause partial androgen insensitivity syndrome. [16]
MAGE-A11 also acts as an isoform-specific coregulator of full-length human progesterone receptor-B through an interaction with the receptor's N terminal. [15] It increases progesterone and glucocorticoid receptor activity, resulting in greater regulatory control over activation domain dominance compared to mice. [7]
Most MAGE-A genes are not expressed in healthy tissues except testicular, ovarian, and placental germ cells. They are expressed in tumor cells. MAGE-A11 in particular shows high expression in a small number of tumors, but low levels in all others. [17]
The MAGE-A family are linked to many kinds of cancerous tumors. MAGE-A11 expression is positively associated with HER-2 expression, and increased MAGE-A11 concentrations are associated with shorter life expectancies of patients with breast cancer. [18]
Increased expression of MAGE-A11 during prostate cancer progression enhances both the androgen receptor signaling pathway and cancer growth. MAGE-A11 mRNA levels increase significantly during androgen deprivation therapy to treat prostate cancer, and MAGE-A11 levels have been found to be highest in castration-recurrent prostate cancer. [15] [19] The drastic increase is the result of DNA hypomethylation of a CpG island in the 5’ promoter of the MAGE-A11 gene. Cyclic AMP has also been found to increase MAGE-A11 expression as well as androgen receptor activity in prostate cancer cell lines, and extensive DNA methylation of the promoter inhibits the effects of cAMP. [19]
The androgen receptor (AR), also known as NR3C4, is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.
The nuclear receptor coactivator 2 also known as NCoA-2 is a protein that in humans is encoded by the NCOA2 gene. NCoA-2 is also frequently called glucocorticoid receptor-interacting protein 1 (GRIP1), steroid receptor coactivator-2 (SRC-2), or transcriptional mediators/intermediary factor 2 (TIF2).
Nuclear receptor coactivator 4, also known as Androgen Receptor Activator (ARA70), is a protein that in humans is encoded by the NCOA4 gene. It plays an important role in ferritinophagy, acting as a cargo receptor, binding to the ferritin heavy chain and latching on to ATG8 on the surface of the autophagosome.
Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 is a protein that in humans is encoded by the NKX3-1 gene located on chromosome 8p. NKX3-1 is a prostatic tumor suppressor gene.
Melanoma-associated antigen 1 is a protein that in humans is encoded by the MAGEA1 gene.
ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.
Melanoma-associated antigen 3 (MAGE-A3) is a protein that in humans is encoded by the MAGEA3 gene.
Melanoma-associated antigen 4 is a protein that in humans is encoded by the MAGEA4 gene.
Protein UXT also known as androgen receptor trapped clone 27 (ART-27) protein is a protein that in humans is encoded by the UXT gene.
E3 ubiquitin-protein ligase RNF14 is an enzyme that in humans is encoded by the RNF14 gene.
Melanoma-associated antigen 2 is a protein that in humans is encoded by the MAGEA2 gene.
Melanoma-associated antigen B2 is a protein that in humans is encoded by the MAGEB2 gene.
Melanoma-associated antigen H1 is a protein that in humans is encoded by the MAGEH1 gene.
Melanoma-associated antigen 12 is a protein that in humans is encoded by the MAGEA12 gene.
Melanoma-associated antigen 9 is a protein that in humans is encoded by the MAGEA9 gene.
Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.
EPI-001 is the first inhibitor of the androgen receptor amino-terminal domain. The single stereoisomer of EPI-001, EPI-002, is a first-in-class drug that the USAN council assigned a new stem class "-aniten" and the generic name "ralaniten". This distinguishes the anitens novel molecular mechanism from anti androgens that bind the C-terminus ligand-binding domain and have the stem class "lutamide". EPI-001 and its stereoisomers and analogues were discovered by Marianne Sadar and Raymond Andersen, who co-founded the pharmaceutical company ESSA Pharma Inc for the clinical development of anitens for the treatment of castration-resistant prostate cancer (CRPC).
Melanoma antigen family A, 8 is a protein that in humans is encoded by the MAGEA8 gene.
Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatogonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.
MAGEA10 is a protein-coding gene in humans clustered at chromosomal location Xq28.