Cancer continues to be a major cause of death in the United States. A primary goal in cancer research is the development of effective treatment strategies targeted at the elimination or inhibition of the growth of cancer cells. A prerequisite to this goal is an understanding of the diverse mechanisms involved in tumor initiation, growth and progression. Central to these mechanisms are the actions, regulation and function of protooncogenes. Mutations which alter the function or regulation of proto- oncogenes activate molecular signaling cascades resulting in the transformation of normal cells into cancer cells. The Jun oncoprotein plays a central role in this process as the nuclear target of a number of signaling pathways. Its function is to convert these signals into changes in gene expression. Because of its role as a transcription regulator, the Jun oncoprotein provides an excellent model to study the process of tumorigenesis at the level of specific gene regulation. The overall objective of this proposal is to gain a better understanding of the molecular mechanisms by which the Jun oncoprotein mediates this process.
The specific aims are; 1, To determine the role of specific AP-1 target recognition in Jun induced cell transformation. 2. To determine the role of the transactivation domain in Jun induced cell transformation. ] 3. To isolate and characterize target genes associated with Jun induced cell transformation. 4. To determine the role of Jun transformation associated genes in oncogenic conversion. The proposal is divided into three parts. The first part (aims 1 and 2) deals with the role of the various biochemical functions of Jun in oncogenic transformation. We have outlined two possible models by which the Jun oncoprotein induces oncogenic transformation. An extensive mutational analysis will be used to distinguish between these models. The second part (aim 30 focuses on identification of the changes in gene expression that occur as a result of oncogenic transformation by Jun. We will isolate and characterize Jun transformation associated target genes using subtractive hybridization and differential display. Molecular characterization of each of these targets will include studies on structure, function and regulation. The third part (aim 4) involves determination of the role that Jun transformation associated targets play in generating a transformed phenotype. This will be accomplished by determining the effect on cell transformation, of overexpression of each target gene. This will determine if each target is sufficient to induce oncogenic conversion. We will also block expression of each target gene, using antisense technology, in order to determine if target genes (that are not sufficient) are required for oncogenic conversion.
