Analysis of the mechanisms and components underlying the coupled cellular processes of signal transduction, transcriptional response and cell growth is the major career interest of the applicant for this research grant. Of particular interest is the mechanism by which oncogene proteins regulate these processes. The activated oncogene is essentially a mutant gene, that provides a phenotype revealing continually new aspects of the behavior, design and interactions of regulatory molecules. In this framework, the proposed research promises to yield new insights concerning the interaction of the E1A oncogene with two dissimilarly regulated genes, interstitial collagenase (CL) and type IV collagenase (T4). The proteolytic enzymes encoded by these genes play an important role in tumor metastasis. E1A protein will be used as a critical probe to analyze their regulation. Specifically, an enhancer element of the CL gene promoter, the TPA- Regulatory Element, was found by this investigator to be an E1A-regulated enhancer: E1A represses its activity in one cell line, but activates it in another. The identification of factors that respond to E1A positively or negatively will be achieved by functionally assaying proteins from one cell system in the background of the other. Assays for this purpose will be of two general types, in vitro (e.g., in vitro transcription) and in vivo (transfection or microinjection.) The T4 gene regulatory region will be analyzed further, as both enhancer and silencer elements have been found. One E1A-repressible enhancer element that binds an AP2-like transcription factor will be characterized in more detail, and the mechanism of E1A repression will be analyzed.
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