The ultimate goal of the experiments proposed here is a better understanding of the mechanism(s) by which avian erythroblastosis virus (AEV) transforms host cells to an oncogenic state. A single locus in the AEV genome, v-erb B, is both required and sufficient for oncogenesis by this virus; the protein product of the v-erb B locus has been identified and partially characterized. The work proposed here seeks to better relate the biochemical and structural properties of the v-erb B protein to the oncogenic abilities of AEV. Three general experimental areas will be pursued: (1) The v-erb B gene will be subjected to in vitro, site-directed mutagenesis to identify regions essential for oncogenesis. The biological effect of various specific genetic lesions will be ascertained. (2) The biochemical properties of the v-erb B protein derived from wild-type and mutant-infected cells will be characterized and compared, and an attempt will be made to correlate specific genetic lesions (from 1, above) with altered structural, biochemical, and oncogenic properties of the v-erb B protein. (3) Chimeras between the v-erb B and v-src oncogenes will be constructed to explore the functional significance of the structural relatedness ascertained between these two retroviral loci. These experiments will provide important information on the molecular biology of the v-erb B protein and will serve as a foundation for a better understanding of the role of this protein in the induction of neoplasms by AEV. This work may also have important implications for comprehension of processes controlling the growth and proliferation of normal eukaryotic cells: the v-erb B protein is closely related (at the amino acid sequence level) to an epidermal growth factor receptor found in uninfected cells.
