The long-term objectives of the research program in Dr. Mertz's laboratory are to understand at the molecular level the mechanisms by which expression of the late genes of SV40 are regulated and the ways in which the virus-encoded oncoprotein, large T antigen, affects expression of these and other genes. During the proposed grant period, the Mertz research group will continue studies aimed at understanding several aspects of this regulation. specifically, they will: (1) determine the mechanism of transcription initiation at the SV40 major late promoter (SV40-MLP) by (a) testing the validity of the """"""""context hypothesis"""""""" for the mechanism of functional binding of TFIID to the -30 region of this promoter, (b) further characterizing and determining the functions of IAP/DAP and IBP, cellular proteins that bind the genetically important initiation site and downstream sequence elements of the SV40-MLP, (c) testing the validity of the hypothesis that initiator elements are simply sequences preferred by RNA polymerase II as start sites for transcription, and (d) beginning identification and determination of the functions of the cellular proteins involved in transcription initiation at the SV40-MLP with a defined in vitro transcription system; and (2) determine the mechanisms by which SV40 large T antigen modulates SV40 late gene expression by (a) identifying the cis-acting sequence elements of the SV40-MLP through which transcriptional transactivation by SV40 large T antigen may be mediated, (b) determining whether direct, genetically important protein-protein interactions occur between SV40 large T antigen and the cellular proteins involved in transcription initiation at the SV40-MLP, (c) identifying the cellular proteins involved in transcription initiation at the SV40-MLP whose specific activities are altered indirectly by SV40 large T antigen, and beginning to determine the mechanism by which one of these alterations occurs, and (d) beginning to determine how SV40 large T antigen post- transcriptionally transactivates expression f the late genes of SV40. These studies should help both to learn about mechanisms by which tumor antigens can alter gene expression in ways that may on occasion lead to the transformation of cells to an oncogenic state and to increase understanding of some of the mechanisms used by eukaryotic cells in regulating gene expression.
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