CONTROL OF PAPILLOMAVIRUS LATE TRANSCRIPTION

乳头状瘤病毒引起良性和恶性的鳞状病变

The papillomaviruses cause benign and malignant lesions of squamous epithelia in higher vertebrates. The complete lytic cycle of these viruses (including late gene expression) occurs only in the differentiated cells of the squamous epithelium. Malignant lesions and infected cells in culture do not produce virus. An understanding of the transcriptional regulation of the papillomaviruses and its relationship to the control of epithelial cell differentiation is necessary for the elucidation of the role of the papillomaviruses in carcinogenesis. We have used bovine papillomavirus type 1 (BPV-1) as a model system for the study of late transcription and its control. Since there are not tissue culture systems which support late transcription, it has been necessary to analyze transcription occurring in the bovine fibropapilloma itself. A full length cDNA library has been constructed frm mRNA isolated from bovine bifropapolloma tissue and has yielded several BPV-1-specific cDNAs not identified in a BPV-1-transformed C127 cell library. Of particular interest is that these mRNAs appear to be transcribed from a papilloma-specific promoter. This has been confirmed by primer extension and nuclease S1 analysis. The "late" or papilloma-specific promoter appears to be as much as 100-fold more active than the promoters used for transcription in BPV-1-transformed cells. We are currently attempting to identify the cis and trans-acting elements which are involved in the control of the late promoter and to determine the role which these trans-acting factors may play in epithelial cell differentiation. A second level of control of late transcription also occurs. Preliminary analysis of transcription occurring in nuclei isolated from BPV-1-transformed cells shows that transcription terminates in the late gene region upstream of the late polyadenylation site, effectively blocking the synthesis of late mRNAs. We are currently attempting to determine what sequences are necessary for transcription termination and to identify any factors which interact in trans with these sequences.