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This version published online on January 13, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0204
A more recent version of this article appeared on May 1, 2005
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Submitted on May 18, 2004
Accepted on January 7, 2005

Cancer Promoted by the Oncoprotein v-ErbA may be due to Subcellular Mislocalization of Nuclear Receptors

Ghislain M. C. Bonamy, Anne Guiochon-Mantel, and Lizabeth A. Allison*

The College of William and Mary, Department of Biology, Williamsburg, Virginia 23187; and INSERM U473 and Université Paris 7 - Denis-Diderot, 2 place Jussieu- 75251 Paris Cedex 05, France; INSERM U473, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275-Le Kremlin-Bicêtre Cedex, France

* To whom correspondence should be addressed. E-mail: laalli{at}wm.edu.

The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor {alpha} (TR{alpha}) which is unable to bind thyroid hormone (T3) 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 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{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.
Key words: v-ErbA • thyroid hormone receptor • retinoid X receptor • oncogene • dominant negative activity

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RXRβ
Ligands:   9-cis-Retinoic acid  |  Thyroid hormone



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