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Cancer Immunity (1 December 2006) Vol Cancer Immun 1424-9634Academy of Cancer Immunology Cancer Immunity (1 December 2006) Vol. 6, p. 12 Submitted: 26 September 2006. Accepted: 10 October 2006. Copyright © 2006 by Andrew J. G. Simpson 061012 Article Physical interaction of two cancer-testis antigens, MAGE-C1 (CT7) and NY-ESO-1 (CT6) Hearn J. Cho1*,**, Otavia L. Caballero2*, Sacha Gnjatic2, Valéria C. C. Andrade3, Gisele W. Colleoni3, Andre L. Vettore4, Hasina H. Outtz1, Sheila Fortunato2, Nasser Altorki1, Cathy A. Ferrera1, Ramon Chua2, Achim A. Jungbluth2, Yao-Tseng Chen1, Lloyd J. Old2 and Andrew J. G. Simpson2 1Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA 2Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA 3Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil 4Ludwig Institute for Cancer Research, Sao Paulo Branch, Sao Paulo, SP, Brazil *These authors contributed equally to this work **Present address: NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA Contributed by: LJ Old Cancer/testis (CT) antigens are the protein products of germ line- encoded on the X chromosome (CT-X antigens) and those that associated genes that are activated in a wide variety of tumors and can are not (non-X CT antigens) (1). elicit autologous cellular and humoral immune responses. CT It is estimated that 10% of the genes on the X-chromosome antigens can be divided between those that are encoded on the X belong to CT-X families (5). CT-X antigens are encoded by chromosome (CT-X antigens) and those that are not (non-X CT genes that have recently undergone rapid evolution and antigens). Among the CT-X antigens, the melanoma antigen gene amplification (6) and are usually highly expressed in (MAGE) family, defined by a shared MAGE homology domain spermatogonia (7, 8, 9). The CT-X genes are frequently (MHD), is the largest. CT-X genes are frequently expressed in a expressed in a coordinate manner in cancer cells (10) and their coordinate manner in cancer cells, and their expression appears to be expression appears to be modulated by epigenetic mechanisms, modulated by epigenetic mechanisms. The expression of CT-X genes such as promoter hypermethylation and histone deacetylation is associated with advanced disease and poor outcome in different (11). tumor types. We used the yeast two-hybrid system to identify In several different tumor types, the expression of CT-X genes putative MHD-interacting proteins. The MHD of MAGE-C1 (CT7) is associated with advanced disease and poor outcome. In non- was used as bait to screen a human testis cDNA library. This study small cell lung cancer (NSCLC), cancer/testis gene expression, identified NY-ESO-1 (CT6) as a MAGE-C1 binding partner. either cumulatively or individually, showed significant Immunoprecipitation and immunofluorescence staining confirmed associations with advanced tumor type, nodal and pathologic MAGE-C1 interaction with NY-ESO-1, and cytoplasmic co- stages, as well as pleural invasion (10). In the same study, the localization of both proteins in melanoma cells. Co-expression of expression of NY-ESO-1 (CTAG1B) and MAGEA3 was each these two genes was found to occur in cancer cell lines from different found to be a marker for poor prognosis, independent of origins, as well as in primary tumors (multiple myeloma and non- confounding variables. Likewise, expression of MAGEA3 in small cell lung cancer samples). This is the first report of direct pancreatic ductal adenocarcinoma was found to be a prognostic interaction between two CT antigens and may be pertinent in the factor for poor survival (12). In colorectal cancers, NY-ESO-1 light of the frequently coordinated expression of these proteins. gene expression may serve as a marker for local metastasis and advanced disease, while expression of MAGEA4 is significantly associated with vessel emboli (13). Similarly, expression of Keywords: two-hybrid assay, MAGE-C1, NY-ESO-1, human, MAGEA1, MAGEA3, MAGEA4, MAGEC1 (CT-7), and multiple myeloma, NSCLC, RT-PCR NY-ESO-1 in malignant gammopathies correlates with stage and risk status of disease (14). Co-expression of SSX1, 2, 4, and 5 also correlates with adverse prognosis in multiple myeloma patients Introduction (15). Immunohistochemistry (IHC) has demonstrated that 82% Cancer/testis antigens (CT antigens) are present in normal of stage III myeloma specimens expressed CT7 and 70% germ line tissues, such as testis, placenta, and ovary and in a expressed MAGE-A3/6, with CT7 protein expression increasing range of human cancers (1). They constitute a promising class of with advanced stage of disease and higher levels of CT7 and tumor antigens due to their limited expression in somatic tissues MAGE-A3/6 proteins being correlated with elevated plasma-cell and strong immunogenicity (2). Cancer/testis antigens have proliferation (16). been isolated by various methods, including cDNA expression Although these data indicate that CT antigen expression might cloning with tumor-reactive CTLs and patients' sera (SEREX), contribute to tumorigenesis, their biological role in both germ cDNA subtractions, and also by EST or MPSS database mining line and tumors remains poorly understood. Recent studies have (2, 3, 4). More than 44 CT genes and/or gene families have been provided some evidence that CT antigens play a role in human identified to date that can be divided between those that are tumorigenesis. Through a yeast two-hybrid assay, the transcriptional regulator SKIP was identified as a MAGE-A1 www.cancerimmunity.org 1 of 8 Cancer Immunity (1 December 2006) Vol. 6, p. 12 binding partner (17). SKIP connects DNA-binding proteins to most family members remains uncharacterized. The cancer/ other proteins that either activate or repress transcription, and testis antigens of the MAGE family are localized in clusters on participates in a range of signaling pathways, including those the X chromosome (22): MAGEA genes at Xq28, MAGEB genes involving vitamin D, retinoic acid, estrogens, glucocorticoids, at Xp21, and MAGEC genes at Xp26-27; these are classified as Notch1 and transforming growth factor-β. In the Notch1 Type I MAGE genes (21). Type II MAGE genes (MAGED, pathway, MAGE-A1 was found to disrupt SKIP-mediated MAGEE, MAGEF, MAGEG, MAGEH and necdin) are expressed Notch1 signal transduction by binding to SKIP and recruiting in many normal tissues at various levels (22). The sequence of histone deacetylase, therefore acting as a transcriptional the MAGE homology domain is a common feature of the Type I repressor. Yeast two-hybrid studies using other cancer-related and II MAGE gene families; it can be found in mammalian genes as bait have twice pulled out MAGE proteins: MAGE-A11 species, as well as in Xenopus, Drosophila, and zebrafish (23). and MAGE-A4 (18, 19). MAGE-A11 was found to have a role in The MHD does not contain any regions of significant homology the regulation of androgen receptor function by modulating its with other known proteins, but detailed analysis of a number of internal domain interactions and was found to have a dual type II MAGE proteins shows that this domain is an important amplifying effect on androgen signaling (18). MAGE-A4 was site for protein–protein interactions (24). The promoters and identified in a search for binding partners of the oncoprotein first exons of the MAGEA genes show considerable variability, gankyrin (19). Gankyrin destabilizes the retinoblastoma tumor suggesting that they are subject to different transcriptional suppressor, contributing to unscheduled entry into the cell cycle controls. and escape from cell-cycle arrest and/or apoptosis. MAGE-A4 To investigate further the function of members of the CT suppresses the oncogenic activity of gankyrin through the action antigen family, we used the yeast two-hybrid system to identify of a peptide that is naturally cleaved from the carboxyl terminus putative MHD-interacting proteins. The MHD of MAGE-C1 of MAGE-A4 and which induces p53-dependent and p53- (CT7) was used as bait to screen a human testis cDNA library. independent apoptosis. Overexpression of MAGEA4 in a human MAGE-C1 is about 800 amino acids longer than the other embryonic kidney cell line (293 cells) was found to increase MAGE proteins and contains a large number of unique short apoptosis as measured by apoptotic index and caspase-3 activity, repetitive sequences in front of the MAGE homologous while MAGEA4 silencing using a small interfering RNA sequence. As a result of this investigation, we identified another approach resulted in decreased caspase-3 activity in a squamous CT antigen, NY-ESO-1 (CT6) as a MAGE-C1 binding partner. cell lung cancer and in 293/MAGE-A4 cells (20). This is the first report of direct interaction between two CT The MAGE family consists of a large group of proteins that antigens and may be pertinent in the light of the frequently harbor the MAGE homology domain (MHD), a well-conserved coordinated expression of these proteins. domain of about 200 amino acids (21). The functional role of Table 1 Potential MAGE-C1/CT7 binding partners identified in the yeast two-hybrid screen 2 of 8 www.cancerimmunity.org Cho et al. Results cancer cell lines. NY-ESO-1 transcripts were detected in 38 (43%) cancer cell lines. In 74% of the cases, there were Identification of proteins interacting with the MHD of MAGE-C1 concordant results (either negative or positive) between (CT7) expression of MAGEC1 and NY-ESO-1. In 28 cell lines (32%), The MHD of MAGE-C1 (CT7) was cloned into a bait both genes were found to be co-expressed. construct and used to screen a high complexity human testis In general, these preliminary results suggested that NY-ESO-1 cDNA library in yeast two-hybrid assays.
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