Protein trafficking across the nuclear envelope is fundamental to cell function. In cancer cells this highly regulated process is often disrupted. This proposal explores aspects of the molecular mechanisms regulating the subcellular distribution of the thyroid hormone receptor (TR) and the oncoprotein v-ErbA. TR is a transcription factor, which activates or represses expression of target genes in response to thyroid hormone (T3). v-ErbA is a mutated variant of TR which interferes with its action in cancer cells and mislocalized it to the cytoplasm. v-ErbA nuclear export is mediated by the export factor CRM1, whereas TR follows a CRM1-independent pathway. Whether TR export is mediated by calreticulin (CRT) and whether v-ErbA has retained the ability to exit the nucleus by this pathway will be examined. Amino acid sequences required for CRT versus CRM1-mediated nuclear export will be investigated. To assess whether experimental conditions induce certain export pathways, as suggested for CRT-mediated steroid receptor export, a combined approach of live cell, cell fusion, and in vitro export assays will be used. The export properties of green fluorescent protein-tagged TR, v-ErbA, and TR/v-ErbA mutant chimeras in wild-type and CRT-deficient mammalian cells will be tracked, v ErbA dominant negative activity is attributed to competition with TR for T3-responsive DNA elements and regulatory factors. However, competition models do not address the altered subcellular localization of v-ErbA and its implications in oncogenesis. The functional significance of cytoplasmic mislocalization of TR by v-ErbA will be investigated in erythroid cells that are a natural target of the viral oncogene. Whether expression patterns of erythroid-specific genes are altered when nuclear export of v-ErbA is blocked will be examined. Results of these studies will increase understanding of the normal cellular response to T3, and provide insight into the ontogeny of an oncogene, and modulation of gene expression through compartmentalization and dominant negative transcription factors.
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