Feedback Regulation between Orphan Nuclear Receptor TR2 and Human Papilloma Virus Type 16

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.Orphan receptors, or receptors without known ligands, make up the vast majority of members of the steroid receptor superfamily (1-3). Members of this family are characterized by a highly conserved DNA-binding domain (DBD) 1 and a carboxylterminal ligand-binding domain. The conserved amino acid sequence within the DBDs of these receptors is predicted to form two zinc finger motifs (1). Additionally, steroid receptors bind to specific DNA sequences known as hormone response elements (HREs) through which regulation of target gene expression may occur (1). The cDNA of the human TR2 orphan receptor (TR2) was isolated from the screening of human testis and prostate cDNA libraries for the androgen receptor. In the screening, an oligonucleotide probe homologous to the highly conserved DBD of the glucocorticoid receptor was used (2). Four TR2 cDNA clones (TR2-5, -7, -9, and -11) were isolated and found to share identical sequences in the N-terminal and DBD regions yet were found to differ in the length of the C-terminal putative ligand-binding domain (3).Through further study of TR2, it was found that this orphan receptor binds to a consensus HRE composed of a direct repeat (DR) with variable spacing (AGGTCAX (n) AGGTCA, n ϭ 0 -6) (4). Using the known TR2 HRE sequence as a guide, it was determined that TR2 has modulatory effects on several signaling pathways such as those involving retinoic acid (4), thyroid hormone (5), and ciliary neurotrophic factor (6). Moreover, expression of the erythropoietin gene (7), aldolase gene (8), histamine H1 receptor (9), and simian virus 40 (SV40) (10) is also regulated by TR2. To add to the list of TR2-responsive genes, we have found a TR2 DR4 consensus site within the long control region (LCR) of the human papilloma virus type 16 (HPV-16). In this report, we show that TR2 is able to bind the consensus response element (DR4RE) within the HPV-16 gene and modulate HPV-16 expression. The human papilloma virus is a common sexually transmitted pathogen that is linked to increased risk for the development of cervical neoplasia, one of the most common cancers in women throughou...

Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4

“…Testicular orphan nuclear receptor 4 (TR4) (also known as TAK1 and Nr2c2; www.informatics.jax.org) is closely related to the retinoid X receptor (RXR), chicken ovalbumin upstream promoter-transcription factor (COUP-TF), and hepatocyte nuclear factor 4 (HNF4) in sequence and structure (2), and binds to AGGTCA DNA sequence motifs in direct repeat orientation, with variable spacing, in the promoters of its target genes. As an orphan nuclear receptor with several known regulatory targets (3)(4)(5)(6)(7)(8)(9)(10)(11), TR4 may affect many signaling pathways and thus have a major impact on physiological function. A substantial difficulty in determining the function of many orphan receptors, including TR4, has been the inability to identify ligands through which the receptors are activated.…”

Suppression of Estrogen Receptor-mediated Transcription and Cell Growth by Interaction with TR2 Orphan Receptor

“…The tumor suppressor genes p53 and Rb which induce cell cycle arrest, can down-regulate TR2 expression in cells after ionizing radiation and in cells overexpressing p53 or Rb (23,24). TR2 can then go through a feedback control mechanism to induce HPV-16 E6 and E7 target gene expression, which are known to enhance the p53 protein degradation and inactivate the Rb function, respectively (23,25). TR2 is, therefore, thought to be involved in the cell cycle regulation.…”

Orphan nuclear hormone receptor NR4A1 interacts with HPV16 E2 regulatory protein

“…Both E2 [17] and NR4A1 [18] are phosphoproteins, the action of which is dependent on the modification [19]. The orphan nuclear receptors emerge to play a significant role in the regulation of viral activity (SV40 [20], MMTV [21], HTLV-1 [22], HIV-1 [23]), and notably, in the case of HPV16 [24]. Further studies on the interaction of these two proteins would give a new insight into the transcription regulation of the HPV16 genome [25].…”