Barettino D, Bugge T H, Bartunek P, Vivanco Ruiz M D, Sonntag-Buck V, Beug H, Zenke M, Stunnenberg H G
EMBL, Gene Expression Programme, Heidelberg, Germany.
EMBO J. 1993 Apr;12(4):1343-54. doi: 10.1002/j.1460-2075.1993.tb05779.x.
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.
V-erbA被认为是甲状腺激素受体（T3R）功能的拮抗剂。在此我们表明，未结合配体的T3R而非v-erbA，通过竞争共同的二聚化伴侣维甲酸X受体（RXR）来抑制视黄酸（RA）依赖的RAR-β2启动子的诱导。首先，共转染RXR可减轻T3R的抑制作用。其次，T3R而非v-erbA，在体外与RAR竞争RXR，并导致预先形成的RAR/RXR-RARE三元复合物解离。位于v-erbA二聚化界面的单点突变（Pro349突变为Ser），当在T3R的相应位置引入时，消除了反式显性表型。这种突变被逆转（Ser349突变为Pro）的高转化性v-erbA变体r12，可抑制鸡红细胞祖细胞中RA诱导的分化，而v-erbA则不能。因此我们的数据表明，未结合配体的T3R和v-erbA通过机制不同的途径发挥显性抑制作用。
