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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038823-02
Application #
3177183
Study Section
Virology Study Section (VR)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Hall, B L; Bonde, B G; Judelson, C et al. (1992) Functional interaction between the two zinc finger domains of the v-erb A oncoprotein. Cell Growth Differ 3:207-16
Sharif, M; Privalsky, M L (1992) V-erbA and c-erbA proteins enhance transcriptional activation by c-jun. Oncogene 7:953-60
Bonde, B G; Sharif, M; Privalsky, M L (1991) Ontogeny of the v-erbA oncoprotein from the thyroid hormone receptor: an alteration in the DNA binding domain plays a role crucial for v-erbA function. J Virol 65:2037-46
Privalsky, M L; Boucher, P; Koning, A et al. (1988) Genetic dissection of functional domains within the avian erythroblastosis virus v-erbA oncogene. Mol Cell Biol 8:4510-7
Boucher, P; Koning, A; Privalsky, M L (1988) The avian erythroblastosis virus erbA oncogene encodes a DNA-binding protein exhibiting distinct nuclear and cytoplasmic subcellular localizations. J Virol 62:534-44
Privalsky, M L (1987) Creation of a chimeric oncogene: analysis of the biochemical and biological properties of v-erbB/src fusion polypeptide. J Virol 61:1938-48
Bassiri, M; Privalsky, M L (1987) Transmembrane domain of the AEV erb B oncogene protein is not required for partial manifestation of the transformed phenotype. Virology 159:20-30
Bassiri, M; Privalsky, M L (1986) Mutagenesis of the avian erythroblastosis virus erbB coding region: an intact extracellular domain is not required for oncogenic transformation. J Virol 59:525-30
Ng, M; Privalsky, M L (1986) Structural domains of the avian erythroblastosis virus erbB protein required for fibroblast transformation: dissection by in-frame insertional mutagenesis. J Virol 58:542-53