The v-erb A oncogene potentiates erythroid transformation and alters the growth properties of fibroblasts. V-erb A is a virus transduced, aberrant copy of a gene for a thyroid hormone receptor. Thyroid hormone receptors (TRs) are ligand-regulated transcription factors, and belong to a larger family of nuclear receptors that play crucial roles in metazoan homeostasis, differentiation, and neoplasia. The v-Erb A protein acts as a transcriptional repressor, inhibiting expression of genes normally activated by TRs and by the closely related retinoic acid receptors (RARs). Therefore, v-erb A has been proposed as a prototype of a novel class of oncogene, acting in cancer as a dominant-negative allele. Similar dominant-negative mutants of nuclear receptors, such as PML-RAR, play important roles in human endocrine disease and cancers. We wish to understand the mechanism of action of the v-erb A oncogene, to relate its role in viral neoplasia to events in normal differentiation, and to use v-erb A as a model to provide new insights into human diseases. A. We will identify v-Erb A and PML-RAR target genes. B. We will determine how v-Erb A represses target gene expression once bound to a target DNA. C. We will determine how v-Erb A function is altered by other signal transduction pathways operative in the erythroleukemic cell. D. V-Erb A will be used as a model to improve our understanding of the actions of the aberrant nuclear receptors involved in human disease. Due to its derivation from a nuclear hormone receptor, v-erb A is one of the most experimentally accessible oncogenes, and holds unusual potential for understanding both neoplasia and the actions of nuclear hormone receptors in the normal organism.
Showing the most recent 10 out of 38 publications
