The v-erb A oncogene of avian erythroblastosis virus potentiates erythroid oncogenic transformation and alters the growth properties of fibroblasts. The v-erb A locus is a virally-transduced and altered copy of a cellular gene for a thyroid hormone receptor. We wish to understand the mechanism of action of the V-erb A oncogene, and to relate its role in virus-induced neoplasias to events in normal cell differentiation and in human cancers. A. The molecular basis behind the activation of the thyroid hormone receptor locus into the v-erb A oncogene will be elucidated. The biochemical differences between the v- and c-erb A proteins will be elucidated and related to the differing oncogenic and transcriptional properties of these two different polypeptides. The role of transcriptional repression by v-erb A in mediating the transformed cell phenotype will be determined, and possible additional mechanisms of action of v-erb A in the neoplastic cell will be investigated. B. The targets of v-erb A action in establishing the transformed state will be characterized. Some evidence suggests that thyroid hormone responsive genes are not the actual physiological targets of v-erb A action in the neoplastic cell; the true targets will be identified. The structural and biological significance of the differing DNA binding properties of the v- and c-erb A proteins will be determined. The nature of cell factors apparently involved in conferring specific DNA binding on the v-erb A protein, and their relationship to similar factors elucidated for the c-erb A protein, will be elucidated. C. The role of thyroid hormone receptors in Xenopus metamorphosis will be determined. The different types of thyroid hormone receptor and receptor- like proteins encoded in the Xenopus genome will be elucidated, and the roles these different gene products play in the tissue specific, temporally regulated process of metamorphosis will be investigated.
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