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Cancer Promoted by the Oncoprotein v-ErbA May Be Due to Subcellular Mislocalization of Nuclear Receptors

The College of William and Mary (G.M.C.B., L.A.A.), Department of Biology, Williamsburg, Virginia 23187; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 693-Récepteurs Stéroïdiens, Physiopathologie endocrinienne et métabolique (G.M.C.B., A.G.M.), Faculté de Médecine Paris Sud, 94276 Le Kremlin-Bicetre Cedex France; and Université Paris 7-Denis-Diderot (G.M.C.B.), 75251 Paris Cedex 05, France

Address all correspondence and requests for reprints to: Lizabeth A. Allison, Department of Biology, College of William and Mary, P.O. Box 8795, Millington Hall 116, Williamsburg, Virginia 23187-8795. E-mail: laalli{at}wm.edu.

The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor (TR), which is unable to bind T₃ and interferes with the action of TR in mammalian and avian cancer cells. v-ErbA dominant-negative activity is attributed to competition with TR for T₃-responsive DNA elements and/or auxiliary factors involved in the transcriptional regulation of T₃-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 and the retinoid X receptor and sequesters a significant fraction of the two nuclear receptors in the cytoplasm. Recruitment of TR 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RXRβ

Ligands:   9-cis-Retinoic acid  |  Thyroid hormone

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