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.
