Cancer promoted by the oncoprotein v-ErbA may be due to subcellular mislocalization of nuclear receptors

The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor alpha (TR alpha), which is unable to bind T-3 and interferes with the action of TR alpha in mammalian and avian cancer cells. v-ErbA dominant-negative activity is attributed to competition with TR alpha for T-3-responsive DNA elements and/or auxiliary factors involved in the transcriptional regulation of T-3-responsive genes. However, competition models do not address the altered subcellular localization of v-ErbA and its possible implications in oncogenesis. Here, we report that v-ErbA dimerizes with TR alpha and the retinoid X receptor and sequesters a significant fraction of the two nuclear receptors in the cytoplasm. Recruitment of TR alpha to the cytoplasm by v-ErbA can be partially reversed in the presence of ligand and when chromatin is disrupted by the histone deacetylase inhibitor trichostatin A. These results define a new mode of action of v-ErbA and illustrate the importance of cellular compartmentalization in transcriptional regulation and oncogenesis.