Structure, chromosomal localization, and expression of 12 genes of the MAGE family (original) (raw)
Related papers
Genomics, 1997
T lymphocytes (CTL) ; De Genes of the MAGE family direct the expression of . The antigen is a nonapeptide tumor antigens recognized on a human melanoma by presented to CTL by MHC-class-I molecule HLA-A1 autologous cytolytic T lymphocytes. Twelve closely re- (Traversari et al., 1992). There are three exons in gene lated MAGE genes are located in the Xq28 region. MAGE-1, and the coding part is entirely contained in These genes share 60-98% nucleotide identity in their the third. MAGE-1 belongs to a family of 12 closely coding region. The presence of homologous genes in related genes located in the q28 region of the X chromoa region of Xp21.3 has been reported previously. We some, and its coding region shows 69-84% nucleotide obtained the complete sequence of a 42-kb stretch of identity with that of the 11 other genes (De Plaen et this region. It contains four MAGE-related genes, Rogner et al., 1995). The MAGE proteins are which we propose to name MAGE-B1, B2, B3, and B4 about 300 amino acids long. Their function is unknown. (HGMW-approved symbols MAGEB1, MAGEB2, MA-Six of the MAGE genes, namely MAGE-1, 2, 3, 4, GEB3, and MAGEB4). The coding regions of these 6, and 12, are expressed in melanomas and also in a genes share 66-81% nucleotide identity and show 45significant proportion of tumors of various histological 63% identity with those of the MAGE genes located in types (Brasseur et al., 1992, 1995; Inoue et al., 1995a, Xq28. Like the MAGE genes located in Xq28, the MAGE-1995b; Mulcahy et al., 1996; Patard et al., 1995; Shich-B genes are silent in normal tissues with the exception of testis. Like ijo et al., 1996;; Weynants proved symbols MAGEA1, 2, 3, 4, 6, and 12), genes et al., 1994). All MAGE genes are silent in all normal MAGE-B1 and MAGE-B2 are expressed in a significant tissues except in testis and, for some, in placenta (De fraction of tumors of various histological types. The De Smet et al., 1994). The expression transcription of MAGE-B1 and MAGE-B2 can be inin testis appears to be restricted to male germ line cells duced by 5-aza-2-deoxycytidine, suggesting that the in the early phase of spermatogenesis: spermatogonia activation of these genes in tumors results from a deand primary spermatocytes (Takahashi et al., 1995). methylation process. ᭧ 1997 Academic Press Because the male germ line cells lack expression of the major histocompatibility complex molecules (Jassim et al., 1989), they are not expected to present MAGE-Recently, Muscatelli and co-workers (1995) reported 1 Present address: Unité INSERM 406, Génétique Médicale et Déthe cloning of a new gene with significant homology to veloppement, Faculté de Médecine de la Timone, boulevard Jean the MAGE gene family located in Xq28. This gene had Moulin 27,
Cancer Research
Human genes expressed exclusively in tumors and male germ line cells, such as those of the MAGE, BAGE, and GAGE families, encode antigens recognized by T lymphocytes, which are potentially useful for antitumor immunotherapy. To identify new genes of this type, we generated cDNA populations enriched in sequences expressed only in testis and melanoma, using the representational difference analysis approach. A testis cDNA library enriched by subtraction with cDNA from four other normal tissues was hybridized with radiolabeled melanoma cDNA enriched by subtraction with normal skin cDNA. A cDNA fragment sharing significant homology with MAGE genes was identified, and a cosmid containing this new gene, named MAGE-C1, was isolated. MAGE-C1 is composed of four exons and encodes a putative protein of 1142 amino acids. It is about 800 residues longer than the other MAGE proteins due to the insertion of a large number of short repetitive sequences in front of the MAGE-homologous sequence. The ...
The Melanoma Antigen Genes—Any Clues to Their Functions in Normal Tissues?
Experimental Cell Research, 2001
The melanoma antigen (MAGE) genes were initially isolated from melanomas and turned out to have an almost exclusively tumor-specific expression pattern. This led to the idea of using MAGE genes as targets for cancer immunotherapy, and MAGE peptides are currently being investigated as immunizing agents in clinical studies. Although 23 human and 12 mouse MAGE genes have been isolated in various tumors and characterized, not much is known about their function in normal cells. In adult tissues, most MAGE genes are expressed only in the testis and expression patterns suggest that this gene family is involved in germ cell development. In contrast to the MAGE genes, more functional data have accumulated around the MAGE related gene necdin. This gene encodes a neuron-specific growth suppressor that facilitates the entry of the cell into cell cycle arrest. Necdin is functionally similar to the retinoblastoma protein and binds to and represses the activity of cell-cycle-promoting proteins such as SV40 large T, adenovirus E1A, and the transcription factor E2F. Necdin also interacts with p53 and works in an additive manner to inhibit cell growth. In this review we will focus on the normal functions of MAGE genes and we speculate, based on the patterns of MAGE expression and on observed functions of necdin, that this gene family is involved in cell cycle regulation, especially during germ cell development.
Expression of MAGE-antigens in normal tissues and cancer
International Journal of Cancer, 2000
The human MAGE gene family encodes products that can be recognized by autologous cytotoxic T cells. Because MAGE genes are silent in most normal tissues except testis but are activated in a variety of neoplastic lesions, MAGE antigens represent ideal targets for immunotherapy. Current knowledge of MAGE gene expression is based primarily on mRNA typing and relatively little is known about MAGE protein expression. Monoclonal antibody (MAb) 57B, originally thought to be specific for MAGE-3, but now known to be reactive with other MAGE components, was used in the present study to analyze MAGE expression in a panel of normal and malignant tissues. In tests with a wide range of normal tissues, only spermatogenic cells of testis were reactive with 57B. In tumor tissues, significant immunoreactivity was observed in malignant melanomas and carcinomas of the lung, head and neck as well as urinary bladder. No 57B reactivity was seen with colorectal, prostatic or renal cell carcinomas. Lipo-and myosarcomas, as well as malignant fibrous histiocytoma (MFH), were negative, but synovial sarcomas showed intense immunoreactivity. A subset of seminomas was also strongly reactive with 57B. Tumor specimens showed great variability in the number of tumor cells showing 57B reactivity, with some tumors showing only small isolated clusters of positive cells to other tumors with uniform staining throughout the tumor. Int. J. Cancer 85: 460 -465, 2000.
The Journal of …, 1995
Human melanoma MZ2-MEL expresses several distinct antigens that are recognized by autologous cytolytic T lymphocytes (CTL). Some of these antigens are encoded by genes MAGE-1, MAGE-3, and BAGE, which are expressed in a large fraction of tumors of various histological types but are silent in normal adult tissues with the exception of testis. We report here the identification of the gene coding for MZ2-F, another antigen recognized by autologous CTL on MZ2-MEL cells. This gene, which was named GAGE-l, is not related to any presently known gene. It belongs to a family of genes that are expressed in a variety of tumors but not in normal tissues, except for the testis. Antigenic peptide YILPRPRRY, which is encoded by GAGE-l, is recognized by anti-MZ2-F CTL on class I molecule HLA-Cw6. The two genes of the GAGE family that code for this peptide, namely GAGE-1 and GAGE-2, are expressed in a significant proportion of melanomas (24%), sarcomas (25%), non-small cell lung cancers (19%), head and neck tumors (19%), and bladder tumors (12%). About 50% of melanoma patients carry on their tumor at least one of the presently defined antigens encoded by the MAGE, BAGE, and GAGE genes.
Immunity
Several tumor antigens are recognized by autologous cytolytic T lymphocytes (CTL) on human melanoma MZ2-MEL. Some of them are encoded by genes MAGE.1 and MAGE.3, which are not expressed in normal tissues except in testis. Here, we report the identification of a new gene that codes for another of these antigens. This gene, named BAGE, codes for a putative protein of 43 aa and seems to belong to a family of several genes. The antigen recognized by the autologous CTL consists of BAGE-encoded peptide AARAVFLAL bound to an HLA-Cw*1601 molecule. Gene BAGE is expressed in 22% of melanomas, 30% of infiltrating bladder carcinomas, 1'0% of mammary carcinomas, 8% of head and neck squamous cell carcinomas, and 6% of non-small cell lung carcinomas. Like the MAGE genes, it is silent in normal tissues with the exception of testis. Because of its tumor-specific expression, the BAGE-encoded antigen may prove useful for cancer immunotherapy.
cDNA and protein characterization of humanMAGE-10
International Journal of Cancer, 1999
MAGE genes are frequently expressed in several types of human malignancy and code for antigens recognized by cytotoxic T lymphocytes. We have previously described a monoclonal antibody (MAb), named 6C1, that recognizes the MAGE-1 protein and cross-reacts with a 72-kDa protein present in lysates of melanoma cells such as MZ2-MEL. To identify this protein, we have screened an expression library prepared from MZ2-MEL cells. Several clones that encoded a protein recognized by antibody 6C1 contained a sequence identical to that of MAGE-10, another member of the MAGE-A gene family. Full-length MAGE-10 cDNA clones, obtained after screening additional cDNA melanoma libraries, were found to be approximately 2.5 kb in length.
Identification and intracellular location of MAGE-3 gene product
1995
The human MAGE-3 gene encodes a melanoma antigenic epitope rec ognized by specific cytotoxic T lymphocytes, but its gene product has not been identified thus far. We produced a recombinant MAGE-3 gene product by expression cloning of the entire reading frame in the context of a fusion protein characterized by a 10-histidine tail, allowing purification by metal chelation on a nickel Sepharose column. The semipurified prod uct was used to generate MAGE-3-specific monoclonal antibodies. One reagent could identify by immunoblotting the native MAGE-3 gene prod uct as a ,l/r 48,000 protein in lysates of cell lines showing evidence of
An Overview of the MAGE Gene Family with the Identification of All Human Members of the Family 1
Cancer Research, 2001
The first human members of the MAGE gene family that have been described are expressed in tumor cells but silent in normal adult tissues except in the male germ line. Hence, they encode strictly tumor-specific antigens that represent attractive targets for cancer immunotherapy. However, other members of the family were recently found to be expressed in normal cells, indicating that the family is larger and more disparate than initially expected. We therefore performed a database screening to identify all of the recorded members of both classes of human MAGE genes. This report provides an overview of the MAGE family and proposes a general nomenclature for all of the MAGE genes identified thus far. We found that the MAGE-D genes were particularly well conserved between man and mouse, suggesting that they exert important functions. In addition, the genomic structure of the MAGE-D genes indicates that one of them corresponds to the founder member of the family, and that all of the other MAGE genes are retrogenes derived from that common ancestral gene. Intriguingly, the COOH-terminal domain of MAGE-D3 was found to be identical to trophinin, a previously described protein believed to be involved in embryo implantation.