Unliganded T3R, but not its oncogenic variant, v‐erbA, suppresses RAR‐dependent transactivation by titrating out RXR.
Unliganded T3R, but not its oncogenic variant, v‐erbA, suppresses RAR‐dependent transactivation by titrating out RXR.
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未配体的 T3R（而非其致癌变体 v-erbA）通过滴定 RXR 来抑制 RAR 依赖性反式激活。
DOI：
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发表时间：
1993
期刊：
影响因子：
11.4
通讯作者：
Hendrik G. Stunnenberg
中科院分区：
文献类型：
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作者：
Domingo Barettino;Thomas H. Bugge;Petr Bartunek;M. D. M. V. Ruiz;Vera Sonntag;Hartmut Beug;Martin Zenke;Hendrik G. Stunnenberg
V-erbA被认为是甲状腺激素受体（T3 R）功能的拮抗剂。在这里，我们表明，未配体的T3 R（而不是v-erbA）通过竞争常见的二聚化伴侣（维甲酸X受体（RXR））来抑制视黄酸（RA）依赖性的RAR-β 2启动子诱导。首先，T3 R抑制可以通过共转染RXR来减轻。其次，T3 R而不是v-erbA与RAR竞争RXR，并导致预先形成的RAR/RXR-RARE三元复合物在体外解离。当在T3 R中的相应位置引入时，位于v‐erbA的二聚化界面（Pro 349至Ser）中的单个点突变消除了反式显性表型。过度转化的v-erbA变体r12，其中该突变被逆转（Ser 349至Pro），抑制RA诱导的鸡红系祖细胞分化，而v-erbA则没有。因此，我们的数据表明，未配体的T3 R和v‐erbA通过不同的机制途径作为显性抑制因子。
V‐erbA is thought to be an antagonist of thyroid hormone receptor (T3R) function. Here we show that unliganded T3R, but not v‐erbA, suppresses retinoic acid (RA)‐dependent induction of the RAR‐beta 2 promoter by competing for the common dimerization partner, the retinoid X receptor (RXR). Firstly, T3R suppression can be alleviated by co‐transfection of RXR. Secondly, T3R, but not v‐erbA, competes with RAR for RXR and causes the dissociation of a preformed RAR/RXR‐RARE ternary complex in vitro. A single point mutation located in the dimerization interface of v‐erbA (Pro349 to Ser) abolishes the transdominant phenotype when introduced at the respective position in T3R. The hypertransforming v‐erbA variant r12, in which this mutation is reversed (Ser349 to Pro) suppresses RA‐induced differentiation in chicken erythroid progenitors, while v‐erbA does not. Our data thus suggest that unliganded T3R and v‐erbA act as dominant suppressors through mechanistically distinct pathways.