Papillomaviruses are found in higher vertebrates and have been associated with benign proliferative lesions. A subgroup of viruses are associated with lesions which can progress to malignancy. There are currently over 65 different human papillomaviruses and six different bovine papillomaviruses. The life cycle of these viruses is closely linked to the differentiation program of squamous epithelial cells which are the natural host cell for these viruses. The bovine papillomavirus type 1 (BPV-1) has served as the prototype of the papillomaviruses for genetic and molecular studies. BPV-1 virus readily transforms a variety of rodent cells in tissue culture, and a unique feature of the transformed cells is that the viral DNA often remains as the stable extrachromosomal plasmid within the cells. The laboratory's studies have been designed to focus on the normal virus host cell interactions of BPV-1 in order to gain insight into the viral and cellular factors which regulate viral gene expression and carcinogenic progression. Recent studies have focused on posttranscriptional regulation of BPV-1 gene expression. Many early region mRNAs are generated by both alternative promoter usage as well as alternative splicing. However, at early stages of the viral life cycle, a 3' splice site at nt 3225 is used almost exclusively, even though other 3' splice sites exist both upstream and downstream of nt 3225. Utilization of this 3' splice site is also regulated during the viral life cycle. Two purine-rich splicing enhancer elements (SE1 and SE2) have been identified between the nt 3225 and nt 3605 3' splice sites. Each is capable of enhancing splicing of a Drosophila doublesex test pre-mRNA in vitro. In addition, SE1 is required for splicing of a BPV-1 pre-mRNA in vitro. A splicing repressor sequence has also been identified downstream of SE1. Both SE1 and SE2 have been shown to bind to members of the SR protein family. Studies are also in progress investigating the functions of the papillomavirus early 3'UTRs and the proteins with which they interact.
