Abstract
The human TR2 orphan receptor (TR2), initially isolated from testis and prostate cDNA libraries, is a member of the steroid receptor superfamily. TR2 can regulate several target genes via binding to a consensus response element (AGGTCA) in direct repeat orientation (AGGTCAX((n))AGGTCA, n = 0-6). Here we show that TR2 is able to induce the expression of human papilloma virus type 16 (HPV-16) genes via binding to a DR4 response element in the long control region of HPV-16. Additionally, one of the HPV-16 gene products, the E6 oncogene, regulates TR2 gene expression. A likely mechanism for this regulation involves E6-mediated degradation of the tumor suppressor p53, a protein known to suppress TR2 expression. Together our data provide evidence for feedback regulation between TR2 and HPV-16, which represents a novel regulatory pathway involving a member of the steroid receptor superfamily and the HPV-16 DNA tumor virus.
Highlights
Receptor binds to a consensus hormone response elements (HREs) composed of a direct repeat (DR) with variable spacing (AGGTCAX(n)AGGTCA, n ϭ 0 – 6) [4]
We report that TR2 is able to modulate the expression of human papilloma virus type 16 (HPV-16) genes and that it does so through binding to a TR2 response element located in the HPV-16 long control region (LCR)
It was clear that TR2 was present in the nuclei of stratified squamous epithelial cells within the regions known to be susceptible to HPV-16 infection (Fig. 1)
Summary
Receptor binds to a consensus HRE composed of a direct repeat (DR) with variable spacing (AGGTCAX(n)AGGTCA, n ϭ 0 – 6) [4]. Receptors without known ligands, make up the vast majority of members of the steroid receptor superfamily [1,2,3] Members of this family are characterized by a highly conserved DNA-binding domain (DBD) and a carboxylterminal ligand-binding domain. Steroid receptors bind to specific DNA sequences known as hormone response elements (HREs) through which regulation of target gene expression may occur [1]. Along with p53 induction, cells demonstrate corresponding cell cycle arrest in phase G1 [15] Relating this to TR2, it has been shown that ionizing radiation represses the expression of the orphan receptor at both transcriptional and translational levels and that this repression is mediated by p53 [16]. The TR2 protein expression kinetics in cells after irradiation was opposite that of p53 expression; TR2 levels decreased dra-
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