THE ERBA ONCOGENE REPRESSES THE ACTIONS OF BOTH RETINOID-X AND RETINOID-A RECEPTORS BUT DOES SO BY DISTINCT MECHANISMS
THE ERBA ONCOGENE REPRESSES THE ACTIONS OF BOTH RETINOID-X AND RETINOID-A RECEPTORS BUT DOES SO BY DISTINCT MECHANISMS
复制标题
DOI：
10.1128/mcb.13.10.5970
复制
发表时间：
1993-10-01
影响因子：
5.3
通讯作者：
PRIVALSKY, ML
中科院分区：
文献类型：
--
作者：
CHEN, HW;PRIVALSKY, ML
在微生物系统中起显性负突变作用的遗传病变早已被认识到。然而，直到最近才发现类似的显性负突变是脊椎动物遗传和肿瘤疾病的基础。我们在这里描述的erbA癌基因蛋白，作为一个显性负抑制剂的其他核激素受体的甲状腺激素受体的异常形式的行动解剖。我们证明，ErbA癌蛋白干扰甲状腺激素和反式维甲酸受体通过竞争结合到相应的反应元件。ErbA癌蛋白与这些受体的异源二聚化在抑制中不起可观察到的作用。然而，相比之下，ErbA癌蛋白确实有效地与类维生素A X受体（RXR）类核激素受体形成异二聚体;复合物的形成增强了ErbA蛋白的DNA结合特性，但显著干扰了RXR组分激活基因表达的能力。我们的研究结果表明，erbA癌基因可能发挥了以前未预料到的作用，通过干扰RXR功能的肿瘤。
Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.