MOLECULAR MECHANISMS OF TRANSFORMATION BY AP 1 PROTEINS

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The Fos and Jun gene families encode a series of proteins that are components of the transcription factor AP-1. The oncogenic potential of this transcription factor is exemplified by the fact that both gene families were originally identified by their presence in the genomes of tumorigenic retroviruses. The Fos-Jun complex is a downstream component of a signal transduction pathway that includes the oncogenic tyrosine kinases and ras oncogenes, and AP-1 activity is induced by events that activate tyrosine kinase or ras activity. Therefore, it seems likely that an understanding of the molecular mechanisms involved in neoplastic transformation by AP-l proteins will also help clarify the events that underlie malignant transformation by these other oncoproteins. Although progress in understanding the molecular mechanisms involved in tumor formation by Fos and Jun proteins has been achieved, several critical questions remain unanswered. Our long term goal is to understand in molecular detail the normal functions of AP-l proteins and how deregulation of this transcription factor contributes to the development of cancer. To reach this goal, we propose specific aims to address the following questions: l) what are the proteins that determine the ability of Fos proteins to activate transcription? Fos family proteins contain a carboxyl-terminal activation domain that is required for transformation. We propose to carry out a mutational analysis to identify critical residues and secondary structures required for function of this domain. This will lead to strategies to identify proteins that interact with this domain and by doing so modulate its function. 2) What is the role of Jun proteins in transformation by Ras proteins? Jun proteins are hypothesized to function as critical mediators of the cellular transforming response to ras. We propose to test this hypothesis genetically, using cells containing null mutations at the c-Jun locus. 3) What are the functional domains required for transformation by AP-1? We will use AP-l proteins with altered dimerization specificity to determine the molecular and biochemical functions required for transformation by AP-l proteins. In addition, we will address non-AP-l determinants of transformation by AP-l proteins.