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

Department of Biology, College of William and Mary, P.O. Box 8795, Millington Hall 116, Williamsburg, VA 23187-8795, USA.
Molecular Endocrinology (Impact Factor: 4.75). 06/2005; 19(5):1213-30. DOI: 10.1210/me.2004-0204
Source: PubMed

ABSTRACT The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor alpha (TRalpha), which is unable to bind T(3) and interferes with the action of TRalpha in mammalian and avian cancer cells. v-ErbA dominant-negative activity is attributed to competition with TRalpha 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 TRalpha and the retinoid X receptor and sequesters a significant fraction of the two nuclear receptors in the cytoplasm. Recruitment of TRalpha 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.

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