Replication of HPVs is of two types. Maintenance replication occurs in basal cells of epithelium, and amplified replication only occurs in superficial layers of papillomas. Stopping maintenance replication would cure infected persons of HPV. Stopping amplified replication would eliminate spread of HPV. The premise of this proposal is that HPV replication is controlled, at least in part, by transcription factors which program differentiation of epithelial cells. Transcription factors control replication by binding at or near sites of initiation, or regulate transcription of proteins needed for replication. The hypothesis to be tested is that transcription factors belonging to the cEBPs family of transcription factors are part of the complex machinery that determines how HPVs replicate. cEBPs direct differentiation. cEBPs are expressed in papillomas and bind to the regulatory region of HPV11. Interleukin 6, which elevates cEBPbeta and cEBP6, is expressed in papillomas and induces proteins in differentiating cells.
Aims will: 1) Determine whether transcription and/or replication of HPV11 DNA can be modulated by dumbbell oligonucleotides to cEBP binding motifs. In vivo assays will use these nuclease resistant oligomers to compete binding of cEBPs to HPV11 DNA. 2) Determine whether HPV replication and/or transcription can be modulated by point mutations of cEBP binding sites in the HPV11 DNA. 3) Determine whether HPV11 transcription and /or replication respond to the levels of cEBPbeta. An expression vector for cEBPbeta or addition of interleukin 6 will be used to change cEBPbeta levels. 4) Identify proteins from undifferentiated and differentiated keratinocytes and papillomas, that interact with the putative cEBP recognition sites in HPV11.
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