Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1.

The human papillomavirus type 18 (HPV‐18) promoter contains a TPA responsive element (TRE) which confers TPA responsiveness on a heterologous promoter. In the context of the HPV‐18 promoter, however, this AP‐1 site is inactive. We have identified a negative regulatory domain in the HPV‐18 promoter which represses the constitutive and TPA‐induced AP‐1 activity. This negative regulatory sequence has been mapped to 44 nucleotides (OL13). We identified this element as a transcriptional silencer based on its ability to interfere with transcriptional initiation. This HPV‐18 silencer domain was narrowed down further to 23 nucleotides, the OL13B element, which bears similarity to three other silencer sequences, present in the mouse N‐ras gene upstream regulatory region, the mouse albumin gene enhancer and the adeno‐associated virus P5 promoter. The transcriptional repressor protein YY1, which negatively regulates the P5 promoter, binds to the HPV‐18 silencer with high affinity. Mutation of the YY1 binding site leads to an enhanced activity of the HPV‐18 promoter, strongly suggesting that YY1 plays an important role in controlling HPV‐18 early gene expression.

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