The upstream regulatory region of the human papilloma virus-16 contains an E2 protein-independent enhancer which is specific for cervical carcinoma cells and regulated by glucocorticoid hormones.

Abstract

The upstream regulatory region of the human papilloma virus‐16 (HPV‐16) genomic DNA contains a sequence element with a large degree of homology to the partially palindromic sequence GGTACANNNTGTTCT, which is the consensus sequence of the glucocorticoid responsive elements of known genes regulated by this steroid hormone. DNase I and dimethylsulfate protection experiments reveal the binding of this sequence by rat glucocorticoid receptor protein. A 400‐bp DNA segment centrally containing this sequence confers strong inducibility by dexamethasone to the promoter p97 of HPV‐16 and to the Herpes simplex virus thymidine kinase promoter, as judged by chloramphenicol acetyltransferase activity and RNase protection assays. The same DNA segment, that does not contain the consensus sequences of all papilloma viruses relevant for E2 protein‐mediated transcription enhancement, functions in an enhancer‐like fashion in addition to its glucocorticoid responsive action. This hormone‐independent transcription enhancement is absent in human MCF7 cells, but is strong in human HeLa cells where the combined activity of the constitutive and the steroid hormone‐dependent enhancer elements stimulate transcription by a factor of 500. This cell type specificity of the HPV‐16 enhancer may be responsible for the tissue tropism of the virus. These observations and the presence of numerous homologies to known enhancers of cellular and viral genes suggest a complex pattern of activation of the human papilloma virus‐16 promoters.

Characterization of keratin and cell cycle protein expression in cell lines from squamous intraepithelial lesions progressing towards a malignant phenotype

“…The growth on plastic of both cell lines became hormone independent at later passages, but the anchorage-independent growth was hormone dependent. Viral transcription is known to be positively regulated by glucocorticoid hormones via the up-stream regulatory region, which may at least partly explain its contributing effect to the transformation (Gloss et al, 1987;Mittal et al, 1993). …”

Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

“…These types of cancers are typically preceded by clinically detectable premalignant, that is, noninvasive lesions that usually arise in epithelial transition zones where cell types are changing. The reasons for the restriction of HPV16-associated tumor development to certain anatomic sites are not clear, but epithelium-specific transcriptional activation of the HPV16 oncogenes (Cripe et al, 1987;Gloss et al, 1987) is likely to play a critical role. More people are infected with HPV16 and HPV18 than develop premalignant lesions and most individuals clear initial infections (IARC, 1995a).…”

Expression of AP1 during cellular differentiation determines human papillomavirus E6/E7 expression in stratified epithelial cells.

“…The activity of this promoter is regulated by transcriptional control elements in the long control region (LCR), which is located upstream of the start site (Gloss et al, 1987). Several nuclear factors have been shown to bind the LCR at specific sites and regulate the transcriptional activity of the promoter, leading to keratinocyte-specific transcriptional activation of HPV.…”