Article

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: 4.2). 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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Available from: Anne Guiochon-Mantel, Aug 22, 2014
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    • "One challenge for the future will be to examine how regulation of this cellular compartmentalization is impaired or altered in the case of aberrant nuclear receptor expression. In addition, defining how nuclear export integrates TRα activity with other signaling pathways may provide important clues as to the mode of action of mutant TRs that are responsible for a host of pathological conditions including cancer (56-58). "
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    ABSTRACT: The thyroid hormone receptor alpha1 (TRalpha) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T(3)). Previously, we have shown that TRalpha, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TRalpha is its ability to exit the nucleus through the nuclear pore complex. TRalpha export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B (LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TRalpha. We show that, in addition to shuttling in heterokaryons, TRalpha shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TRalpha directly interacts with calreticulin, and point to the intriguing possibility that TRalpha follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TRalpha from the nucleus to cytoplasm.
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    • "Indeed, we have observed that v-ErbA is able to modulate the TGF-β signalling pathway in T2ECs (Gonin-Giraud et al., submitted). These data suggest a role for v-ErbA in intracellular signalling pathways in agreement with its cytoplasmic localisation [33]. "
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