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The Homeotic Protein Six3 Is a Coactivator of the Nuclear Receptor NOR-1 and a Corepressor of the Fusion Protein EWS/NOR-1 in Human Extraskeletal Myxoid Chondrosarcomas¹

Human and Molecular Genetic Research Unit, Pavillon Saint-François d’Assise, CHUQ, Quebec, Qc, G1L 3L5 and Laval University Faculty of Medicine, Quebec, Qc, G1K 7P4 Canada [C. L., C. F., Y. L.]; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198 [J. A. B.]; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [M. L.]; and New England Baptist Bone and Joint Institute and Rheumatology Division, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115 [M. B. G.]

Nuclear receptors represent a large family of transcription factors involved in development, differentiation, homeostasis, and cancer. In recent years, a growing number of cofactors has been discovered that participate in the regulation of the transcriptional activity of these proteins. We present in this study the identification of a cofactor, the homeotic protein Six3, which differentially regulates the transcriptional activity of the orphan nuclear receptor NOR-1 (NR4A3). NOR-1 is normally involved in the balance between cell proliferation and cell death, and is implicated in oncogenesis as part of the EWS/NOR-1 fusion protein found in human extraskeletal myxoid chondrosarcoma (EMC) tumors. Reverse transcription-PCR analyses indicate that EMC tumors expressing the EWS/NOR-1 mRNA also express mRNAs encoding NOR-1 and Six3. Glutathione S-transferase fusion protein assays show that Six3 binds in vitro the DNA-binding domain of NOR-1 and the EWS domain of EWS/NOR-1 and that the homeodomain of Six3 is required for these interactions. Mammalian two-hybrid experiments, using immortalized human chondrocytes as a model, indicate that Six3 also interacts with NOR-1 and EWS/NOR-1 in vivo. Cotransfection experiments show that Six3 stimulates the transcriptional activity of NOR-1, whereas it represses that of EWS/NOR-1. Considering the highly specific expression pattern of Six3, our finding that it is expressed in EMC suggests that it plays a pivotal role in the development of these tumors. We propose that Six3 maintains a transcriptional balance between the activities of NOR-1 and EWS/NOR-1, the net effect being to deregulate the expression of specific target genes and push the equilibrium toward uncontrolled cell proliferation.

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