Cancer is a malady of genes. Understanding the molecular basis of neoplastic transformation requires an in depth analysis of the structure and function of the implicated genes. Nearly two score cellular genes (proto-oncogenes) have been identified whose altered or unregulated products can cause cellular transformation. My laboratory has chosen to focus on proto-oncogene fos (c-fos) a paradigm of nuclear oncogenes. We want to study the molecular mechanisms required to convert this seemingly essential gene to become a transforming gene. We propose to study the regulation of transcription of proto-oncogene fos in response to a variety of inducible agents. We plan to delineate the sequences and cellular factors required in turning on and off the c-fos gene. We also propose to investigate the post-transcriptional regulation of the c-fos gene. Specifically, we are interested to investigate the mechanisms controlling the short half-life of c-fos mRNA. We plan to study the post-translational control of the fos product by identifying the biochemical nature of the modifications. An in depth analysis of the transforming fos protein is proposed with the aim of identifying the region of the protein required for biochemical function. The role of the fos protein in normal cells would be studied with the aid of anti-sense for RNA and anti-sense oligonucleotides. We have proposed experiments to study the effect of fos protein in a variety of hematopoietic tissues by infecting stem cells with fos retroviruses. We would also like to study the tissue tropism of the c-fos gene by generating transgenic mice. Attempts would also be made to isolate and analyze the cellular protein, p39, which non-covalently precipitates with fos protein. Finally, experiments are proposed to study regulation of the expression of proto-oncogene fms. We feel the proposed studies would advance our knowledge of the molecular mechanisms involved in tumorigenesis. We plan to construct high efficiency retroviral vectors to transfer genes into cells and whole animals. In particular, we plan to introduce foreign genes in mouse bone marrow, skin and fibroblasts. We plan to use a retrovirus containing Factor IX (hemophilia B) gene as a model system. One of our goals is to develop high efficiency, safe retroviral vectors which may be used for human somatic cell gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA044360-06
Application #
3479585
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1988-05-01
Project End
1994-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Somia, N V; Schmitt, M J; Vetter, D E et al. (1999) LFG: an anti-apoptotic gene that provides protection from Fas-mediated cell death. Proc Natl Acad Sci U S A 96:12667-72
Miyoshi, H; Smith, K A; Mosier, D E et al. (1999) Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science 283:682-6
Wisdom, R; Verma, I M (1993) Proto-oncogene FosB: the amino terminus encodes a regulatory function required for transformation. Mol Cell Biol 13:2635-43
Wisdon, R; Verma, I M (1993) Transformation by Fos proteins requires a C-terminal transactivation domain. Mol Cell Biol 13:7429-38
Roman, M; Axelrod, J H; Dai, Y et al. (1992) Circulating human or canine factor IX from retrovirally transduced primary myoblasts and established myoblast cell lines grafted into murine skeletal muscle. Somat Cell Mol Genet 18:247-58
Miyanohara, A; Johnson, P A; Elam, R L et al. (1992) Direct gene transfer to the liver with herpes simplex virus type 1 vectors: transient production of physiologically relevant levels of circulating factor IX. New Biol 4:238-46
Wisdom, R; Yen, J; Rashid, D et al. (1992) Transformation by FosB requires a trans-activation domain missing in FosB2 that can be substituted by heterologous activation domains. Genes Dev 6:667-75
Link, E; Kerr, L D; Schreck, R et al. (1992) Purified I kappa B-beta is inactivated upon dephosphorylation. J Biol Chem 267:239-46
Bull, P; Morley, K L; Hoekstra, M F et al. (1990) The mouse c-rel protein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain. Mol Cell Biol 10:5473-85