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 (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.
Bonamy
Ghislain M C
GM
Department of Biology, College of William and Mary, P.O. Box 8795, Millington Hall 116, Williamsburg, VA 23187-8795, USA.
Guiochon-Mantel
Anne
A
Allison
Lizabeth A
LA
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D018774:Oncogene Proteins v-erbA / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D049230:Retinoid X Receptor beta / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
D006655:Histone Deacetylases; D006657:Histones; D028884:Karyopherins; D008024:Ligands; D018774:Oncogene Proteins v-erbA; D018160:Receptors, Cytoplasmic and Nuclear; D049230:Retinoid X Receptor beta; D037021:Thyroid Hormone Receptors alpha; D000097606:Exportin 1 Protein