Abstract

This Project is a joint effort of four investigators to study how tissue- specific expression of oncogene products relates to oncogenesis. Much of the effort can be categorized under three questions: What are the functions of oncogenes? How can oncogene expression be controlled to give tissue-specific activation in animals? What are the consequences of the tissue-specific expression of different oncogenes? The oncogenes that will be of primary interest will be ab1, myc, and ras. The role of myc in preventing differentiation will be an important theme. The role the tyrosine-specific kinase encoded by ab1 will be studied using both genetics and biochemical methods. Recombinant DNA methods will be used to develop retrovirus-based vectors for integrating oncogenes into embryonic cells of the mouse fetus. By inserting appropriate control regions into the vectors, tissue-specific expression of the oncogenes will be attempted to allow the oncogenic spectrum of each oncogene to be ascertained. A prominent system for obtaining tissue-specific transcriptional signals will be the immunoglobulin genes. Vectors will be integrated into both pre-implantation and post- implantation mouse embryos to study their properties in both early and later fetal cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA038497-05
Application #
3093674
Study Section
Cancer Special Program Advisory Committee (CAK)
Project Start
1984-12-01
Project End
1989-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142

  Publications

Sharpe, A H; Jaenisch, R (1993) Retroviral spongiform degenerative disease produced by the murine neurotropic retrovirus Cas-Br-E. Dev Biol Stand 80:45-52
Kobayashi, H; Man, S; Graham, C H et al. (1993) Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci U S A 90:3294-8
Daley, G Q; Van Etten, R A; Baltimore, D (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247:824-30
Teicher, B A; Herman, T S; Holden, S A et al. (1990) Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247:1457-61
Stuhlmann, H; Jaenisch, R; Mulligan, R C (1989) Transfer of a mutant dihydrofolate reductase gene into pre- and postimplantation mouse embryos by a replication-competent retrovirus vector. J Virol 63:4857-65
Yang, X M; Martinez, R; Le Beau, J et al. (1989) Evolutionary expression of the neuronal form of the src protein in the brain. Proc Natl Acad Sci U S A 86:4751-5
Jackson, P; Baltimore, D (1989) N-terminal mutations activate the leukemogenic potential of the myristoylated form of c-abl. EMBO J 8:449-56
Van Etten, R A; Jackson, P; Baltimore, D (1989) The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell 58:669-78
Stuhlmann, H; Jaenisch, R; Mulligan, R C (1989) Construction and properties of replication-competent murine retroviral vectors encoding methotrexate resistance. Mol Cell Biol 9:100-8
Kelley, S L; Basu, A; Teicher, B A et al. (1988) Overexpression of metallothionein confers resistance to anticancer drugs. Science 241:1813-5

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