The adenovirus E1a protein is a potent activator of early viral gene transcription and can also modulate cellular gene expression. Transcription directed by the adenovirus E1a protein provides a powerful model to study the mechanisms involved in gene regulation in higher eukaryotes. Over the past budget period we have made significant progress in our major goal of understanding how E1a activates transcription. In particular, we have delineated functional domains of the E1a protein; developed a model for how E1a activates transcription of viral early genes; identified the ATF family of cellular transcription factors; isolated cDNA clones for multiple ATF proteins; and begun to characterize the activities of individual ATFs. These studies have led to the identification of one ATF protein, ATF-2, which can support Ela-directed transcription. Over the next budget period we will develop and expand upon these results in greater detail. In particular, we are interested in identifying, purifying and cloning cellular components that interact with regions of El a critical for transcriptional function. We propose a series of in vivo experiments that will test and refine our understanding of how E1a activates transcription. To analyze these mechanisms in further detail we will attempt to establish in vitro systems that support E1a-mediated transcriptional activation. A variety of experiments are proposed to characterize further the activities and functions of specific members of the ATF transcription factor family. In summary, we propose a broad and comprehensive set of experiments the results of which should enrich our knowledge about the adenovirus E1a protein and the cellular proteins through which E1a acts.
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