title: Requirements for repression of retinoid X receptor by the oncoprotein P75gag-v-erbA and the thyroid hormone receptors.
abstract: The oncogenic counterpart of thyroid hormone receptor-alpha (TRRalpha), denoted P75gag-v-erbA, has served as a paradigm for the ability of TRs to repress basal levels of transcription. We show here that the retinoid X receptor (RXR), when activated by its specific ligand SR11237, is repressed by both the normal TRalpha and the P75gag-v-erbA. The repression caused by the two proteins is distinct and dependent on both the cell type and the hormone-response element through which RXR acts. In HeLa cells only TR repressed efficiently through the palindromic 2xIR0 element, whereas the proteins were equally efficient in JEG cells. This demonstrates that proteins distinct in the two cell types mediate the repression. RXR-dependent induction via the natural response element of the cellular retinol-binding protein (CRBPII) gene was likewise (> or = 50%) repressed by TR, whereas P75gag-v-erbA did not repress during the same conditions. Furthermore, P75gag-v-erbA and its variants v-erbAtd359 (lacking repressing activity on TR) and v-erbAr12 (a highly active repressor of TR) efficiently repressed induction by a hybrid protein consisting of the DNA- binding domain of Gal4 and the ligand-binding region of RXR. The viral proteins did not, however, associate with RXR unless the two partners were allowed to heterodimerize upon binding to a specific response element, such as the 2xIR0 element or that of the CRBPII gene. In conclusion, we suggest that the efficient repression seen with the the 2xIR0 element is due to heterodimerization of TR or the viral oncoproteins with RXR and a concomitant inhibition of binding of the RXR-specific ligand that results in an inability of RXR to attract a cell type-specific cofactor. In addition, the data suggest that the interaction between RXR and P75gag-v-erbA on the CRBPII element is too weak to inhibit RXR from binding a ligand and therefore also to repress.
authors.affiliation: Department of Cellular and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: G M
authors.initials: GM
authors.lastname: Wahlström
authors.forename: B
authors.initials: B
authors.lastname: Vennström
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002822:Choriocarcinoma; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018774:Oncogene Proteins v-erbA / Q000235:genetics / Q000502:physiology*; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D018774:Oncogene Proteins v-erbA; D016761:Oncogene Proteins v-fos; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D004247:DNA