The goal of this project is to understand mechanisms of transcriptional activation by viral transactivators. By altering patterns of transcriptional regulation, DNA viruses can manipulate cellular gene expression and consequently transform cells. Upon infection, viral gene products frequently associate with cellular factors to effect these changes. In some instances, these associations involve interactions between the products of viral oncogenes, such as the adenovirus E1 gene products and SV40 T antigen, and cellular tumor suppressors, such as the product of the retinoblastoma susceptibility gene, p105RB, and p53, that are probably also transcriptional regulators. In this project, we use the cellular transcription factor Oct-1 as a probe to study mechanisms of viral transactivation. Oct-1 is the target of transactivation by VP16, the herpes simplex virus (HSV) activator of immediate-early (IE) gene transcription. VP16 induces formation of multiprotein-DNA complex by associating with Oct-1 and a second host cell factor called HCF. In forming this multiprotein-DNA complex, VP16, by virtue of possessing a powerful transcriptional activation domain, serves as a transcriptional adaptor that induces activation of transcription by Oct-1. In this project, we will study in detail the interactions between VP16, HCF, and DNA, and study how the DNA tumor virus oncoproteins E1A and T antigen may also influence Oct-1 activity. We will (i) determine how Oct-1, VP16, and HCF interact with DNA either alone or when bound as a complex; (ii) characterize the regions of VP16 responsible for assembly of the complex and the regions of Oct-1 that are involved in stimulating transcription in the VP16-induced complex; (iii) determine the structure and function of HCF; and (iv) assay the effects of SV40 and adenovirus infection of Oct-1 function. These studies will illuminate the mechanisms by which viral transactivators can influence the cellular transcriptional apparatus.
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