The objectives are to understand the molecular level some of the transcriptional and post-transcriptional mechanisms that regulate expression of genes of simian virus 40 (SV40), herpes simplex virus type 1 (HSV-1), hepatitis B virus (HBV) and, eventually, other clinically relevant tumor viruses. The first specific aim is to determine the functions and mechanisms of action of action of the pre-mRNA processing enhancer (PPE) of the thymidine kinase gene of HSV, a human immunodeficiency virus (HIV) Rev-response-like element, and its HIV Rev- like cellular trans-acting factor, the heterogeneous nuclear-ribonuclear protein (hnRNP) L, in the processing and nuclear export of pre-mRNAs and their utility in the expression of complementary DNAs by (a) identifying the nuclear export of pre-mRNAs and their utility in the expression of complementary DNAs by (a) identifying the bases involved in PPE function, (b) determining the functions and mechanisms by which hnRNP L mediates intro-independent mRNA biogenesis via binding this PPE, (c) identifying additional PPE-like elements in other intronless genes, and (d) determining the generality of PPEs enabling efficient intron-independent gene expression in mammalian cells. The second and third specific aims are to determine the mechanisms by which members of the steroid/thyroid hormone receptor superfamily and their ligands affect expression and replication of SV40 of the steroid/thyroid hormone receptor superfamily and their ligands affect expression and replication of SV40 and HBV by (a) examining the effects on transcription and virion production of some nuclear receptors that bind promoters of these two viruses and the ligands for these receptors, and (b) determining the mechanisms by which specific nuclear receptors, their ligands, the SV40 encoded oncoprotein large T- antigen, and a cellular factor, DAP, regulated transcription from the SV40 major late promoter. A variety of biochemical, molecular, genetical, and cellular techniques will be used. The findings from these studies should not only increase our understanding of fundamental mechanisms involved in regulation of mRNA biogenesis in viruses and mammals, but may also lead to the development of novel drugs for the treatment of diseases caused by viruses and improved vectors for use in gene therapy and the manufacture of biologically useful proteins.
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