Wahlström G M, Vennström B
Department of Cellular and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Mol Endocrinol. 1998 May;12(5):645-53. doi: 10.1210/mend.12.5.0096.
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.
甲状腺激素受体α（TRα）的致癌对应物，即P75gag-v-erbA，已成为TRs抑制基础转录水平能力的范例。我们在此表明，视黄酸X受体（RXR）在被其特异性配体SR11237激活时，会受到正常TRα和P75gag-v-erbA的抑制。这两种蛋白质引起的抑制作用是不同的，并且取决于细胞类型以及RXR作用的激素反应元件。在HeLa细胞中，只有TR能通过回文2xIR0元件有效抑制，而在JEG细胞中这两种蛋白质的抑制效果相同。这表明在两种细胞类型中发挥作用的蛋白质介导了抑制作用。通过细胞视黄醇结合蛋白（CRBPII）基因的天然反应元件进行的RXR依赖性诱导同样（≥50%）受到TR抑制，而在相同条件下P75gag-v-erbA没有抑制作用。此外，P75gag-v-erbA及其变体v-erbAtd359（对TR缺乏抑制活性）和v-erbAr12（TR的高活性抑制剂）能有效抑制由Gal4的DNA结合结构域和RXR的配体结合区域组成的杂合蛋白的诱导作用。然而，除非这两个伙伴在与特定反应元件（如2xIR0元件或CRBPII基因的元件）结合时允许异源二聚化，否则病毒蛋白不会与RXR结合。总之，我们认为通过2xIR0元件观察到的有效抑制是由于TR或病毒癌蛋白与RXR的异源二聚化以及随之而来的RXR特异性配体结合的抑制，这导致RXR无法吸引细胞类型特异性辅因子。此外，数据表明RXR与CRBPII元件上的P75gag-v-erbA之间的相互作用太弱，无法抑制RXR与配体的结合，因此也无法抑制。
