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.

Differential HPV16 variant distribution in squamous cell carcinoma, adenocarcinoma and adenosquamous cell carcinoma

“…2,50 Some authors have identified polymorphisms in HPV16_D variants glucocorticoid response elements (GREs) 50-52 that confer facilitated activation of promoter p97, leading to an enhanced E6-E7 transcription activity. [50][51][52][53] An alternative hypothesis would be that the cellular targets for malignization associated preferentially to HPV16_A1-3 variants are rarer in glandular epithelia. The existence of particular cell types associated with the development of ICC is well documented.…”

Persistent HPV infection in postmenopausal age women

“…The adverse effects of using HRTs for long duration and subsequent development of cervical squamous epithelial neoplasia (SIL) are unknown and it is unclear whether their effects will mimic those found for OCs. The in vitro evidence indicates that there is greater HPV gene expression and cell transformation by the viral DNA in the presence of progesterones [13][14][15].…”

Risk factors inducing the persistence of high‐risk genital papillomaviruses in the normal cervix

“…The model which best fitted these data was that using some specific oral contraceptives as response predictor (r = 0.218 instead of T = 0.117 for all oral contraceptives taken together). This is not surprising if the recent observations of Chan et al [1989] are considered. They identified in the long control region of the genome of the most frequently detected genital HPV DNA segment which functions as a cell type-specific enhancer as well as glucocorticoidi progesterone response element (GREIPRE).…”