Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia

Abstract

We have previously identified in the long control region of the genome of human papillomavirus type 16 (HPV-16) a DNA segment which functions as a cell-type-specific enhancer as well as mediating glucocorticoid response. It contains multiple transcription-factor-binding sites, including several for nuclear factor I and one for the glucocorticoid receptor, which binds to the partially palindromic sequence TGTACANNNTGTCAT. We report here that this sequence element, when separated from the surrounding transcription-factor-binding sites and placed as an oligonucleotide into a test vector, retains its function as a glucocorticoid response element (GRE) in HeLa cells. In T47D cells, which express the progesterone receptor, the HPV-16 enhancer fragment mediates progesterone responsiveness. A point mutant in this fragment and the response of the oligonucleotide clone to both steroids prove the identity of the progesterone response element (PRE) with the GRE. The antiprogesterone and antiglucocorticoid RU486 interferes with both hormonal responses. In SiHa cells, the HPV-16 GRE mediates an increase in transcripts encoding E6 and E7 proteins, which are involved in transformation by HPV-16. Hormonal regulation is not restricted to HPV-16: DNA segments containing the cell-type-specific enhancers of HPV-11 and HPV-18 also mediate glucocorticoid and progesterone response. We identified sequence elements in the long control regions of HPV-11 and HPV-18 which function as GRE/PREs when tested as oligonucleotides. These findings suggest that GRE/PREs are an integral part of gene expression regulation in genital HPVs.