The AF2 domain of the orphan nuclear receptor TEC is essential for the transcriptional activity of the oncogenic fusion protein EWS/TEC.
The EWS/TEC fusion protein encoded by the t(9:22) chromosomal translocation in human extraskeletal myxoid chondrosarcoma tumors is thought to participate in the tumoral process at least in part by deregulating the expression of specific target genes involved in the control of cell proliferation. In this work we show that the activation function-2 (AF2) domain of TEC is essential for the transcriptional activity of the EWS/TEC fusion protein. Significantly, deleting only the last 15 amino acids of the fusion protein, which contains 949 amino acids in its full form, results in a loss of over 70% of its transcriptional activity in transfected human chondrocyte cell lines. Point mutation analyses indicate that within the AF2 domain, amino acid residues I939, D940 and F943 all play a crucial role in the activity of EWS/TEC. Comparable results were obtained with the native TEC receptor. These results suggest that EWS/TEC interacts at least in part with the same transcriptional coactivators as the native TEC receptor, and that these coactivators may be involved in the tumoral process leading to human chondrosarcoma tumors.
Maltais
Annie
A
Unité de Recherche en Génétique Humaine et Moléculaire, Pavillon Saint-François d'Assise, CHUQ, 10 rue de l'Espinay, G1L 3L5, Québec, QC, Canada.
Filion
Christine
C
Labelle
Yves
Y
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001859:Bone Neoplasms / Q000235:genetics; D002813:Chondrosarcoma / Q000235:genetics; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014162:Transfection; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D009687:Nuclear Proteins; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins