The v-erbA oncogene of avian erythroblastosis virus is an aberrant copy of a gene for a thyroid hormone receptor. V-erbA can act as a transcriptional repressor, inhibiting expression of genes normally activated by thyroid hormone receptors. Therefore, v-erbA represents a novel class of oncogene, acting in cancer as a dominant negative allele.Dominant negative mutants of nuclear hormone receptors also play important roles in human endocrine and neoplastic diseases. The main objective of this proposal is to understand the mechanism of action of the v-erbA oncogene, and to relate its role in viral neoplasia to event in normal differentiation and in human disease. A. The targets of v-erbA action in the neoplastic cell will be identified. The following questions will be addressed: 1) What is the optimal DNA binding site for the v-erbA protein? 2) What role does the altered DNA binding specificity of v-erbA play in the neoplastic phenotype?3) What genes are actually regulated by the v-erbA protein in the erythroleukemic cell? B. The molecular basis for the altered DNA binding specificity of the v-erbA protein will be elucidated. C. The interaction of v- and c- erbA proteins with other important regulatory polypeptides will be investigated.In particular: 1) What is the molecular basis behind the different interaction of the v- and c-erbA proteins with one another and with RXRs? 2) What other regulatory factors interact with v- and c-erbA proteins to influence their functions? D. The v-erbA protein will be used as a probe to elucidate the role of retinoic X receptors in Xenopus and murine development.
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