The discovery of oncogenes revolutionized analysis of the molecular bases of cancer. Oncogenes provided starting points for molecular dissection of the signaling pathways that govern normal cell growth and for elucidation of the events that lead to oncogenesis. The fos oncogene is responsible for induction of osteosarcomas and cell transformation by the Finkel-Biskis-Jinkins murine sarcoma virus. Its protein product, Fos, functions as a component of the inducible mammalian transcription factor AP 1. Induction of c-fos expression is associated with mitogenesis, differentiation, apoptosis and excitation of neurons. It is believed to participate in complex signal transduction networks that couple extracellular stimuli to long-term cellular responses by regulating gene expression. Transformation by fos is thought to be a consequence of inappropriate regulation of gene expression. Three major specific aims are addressed in this application. The first concerns the identification and characterization of fos target genes responsible for cell transformation by Representational Difference Analysis and cDNA array hybridization approaches. In the second specific aim we will follow up preliminary studies demonstrating that DNA 5-methylcytosine transferase-1 (dnmt1) is a fos target gene involved in cell transformation. We plan to identify genes that are methylated by dnmt1 in fos transformed cells and analyze their contribution to transformation. The third specific aim concerns the role of reduction/oxidation (redox) in the regulation of Fos function and cell growth. Previously, we demonstrated that the bifunctional redox/endonuclease gene, ref-1, regulates the DNA binding activity of Fos through a conserved cysteine residue in the DNA binding domain. Disruption of the Ref-1 gene in mice causes early embryonic lethality. We will introduce point mutations into Ref-1, by homologous recombination in embryonic stem cells that ablate the redox and nuclease functions of Ref-1 independently. These cells will be used to generate mutant mice and cell lines that will be used to analyze the role of Ref-1 in modulating AP1 activity and cell growth.
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