Point mutations in SP1 motifs in the upstream regulatory region of human papillomavirus type 18 isolates from cervical cancers increase promoter activity.

Rose, Barbara; Steger, Gertrud; Dong, Xiao-Ping; Thompson, Carol H.; Cossart, Yvonne E.; Tattersall, Martin H. N.; Pfister, Herbert

doi:10.1099/0022-1317-79-7-1659

Cited by 23 publications

(24 citation statements)

References 19 publications

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“…Consistent with previous findings reporting Sp1 to be a key activator of RNA polymerase II-dependent promoters in HPV (43,52), introduction of a mutation into its binding site caused a significant decrease in LCR promoter activity, which was no longer repressed by IFI16 overexpression. These results indicate that the Sp1 binding site could constitute a target of IFI16.…”

Section: Resultssupporting

confidence: 80%

The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters

Cigno

Andrea

Borgogna

et al. 2015

J Virol

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The human interferon-inducible IFI16 protein, an innate immune sensor of intracellular DNA, was recently demonstrated to act as a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1) infection by inhibiting both viral-DNA replication and transcription. Through the use of two distinct cellular models, this study provides strong evidence in support of the notion that IFI16 can also restrict human papillomavirus 18 (HPV18) replication. In the first model, an immortalized keratinocyte cell line (NIKS) was used, in which the IFI16 protein was knocked down through the use of small interfering RNA (siRNA) technology and overexpressed following transduction with the adenovirus IFI16 (AdVIFI16) vector. The second model consisted of U2OS cells transfected by electroporation with HPV18 minicircles. In differentiated IFI16-silenced NIKS-HPV18 cells, viral-load values were significantly increased compared with differentiated control cells. Consistent with this, IFI16 overexpression severely impaired HPV18 replication in both NIKS and U2OS cells, thus confirming its antiviral restriction activity. In addition to the inhibition of viral replication, IFI16 was also able to reduce viral transcription, as demonstrated by viralgene expression analysis in U2OS cells carrying episomal HPV18 minicircles and HeLa cells. We also provide evidence that IFI16 promotes the addition of heterochromatin marks and the reduction of euchromatin marks on viral chromatin at both early and late promoters, thus reducing both viral replication and transcription. Altogether, these results argue that IFI16 restricts chromatinized HPV DNA through epigenetic modifications and plays a broad surveillance role against viral DNA in the nucleus that is not restricted to herpesviruses. IMPORTANCEIntrinsic immunity is mediated by cellular restriction factors that are constitutively expressed and active even before a pathogen enters the cell. The host nuclear factor IFI16 acts as a sensor of foreign DNA and an antiviral restriction factor, as recently demonstrated by our group for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1). Here, we provide the first evidence that IFI16 inhibits HPV18 replication by repressing viral-gene expression and replication. This antiviral restriction activity was observed in immortalized keratinocytes transfected with the religated genomes and in U2OS cells transfected with HPV18 minicircles, suggesting that it is not cell type specific. We also show that IFI16 promotes the assembly of heterochromatin on HPV DNA. These changes in viral chromatin structure lead to the generation of a repressive state at both early and late HPV18 promoters, thus implicating the protein in the epigenetic regulation of HPV gene expression and replication. Many recent studies point to the importance of cell-type-and host-specific expression of antiviral factors in limiting viral infection (1-4). Some of the very early antiviral responses include the activation of intrinsic restriction factors at h...

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Section: Resultssupporting

confidence: 80%

The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters

Cigno

Andrea

Borgogna

et al. 2015

J Virol

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“…However, other studies analyzing nucleotide variability in the LCR, E2, or E6/E7 genes found no correlation between HPV-18 genotypes and lesion grade (31,32). Intratypic variability among HPV-18-positive specimens from North American and Mexican women suggested an association between specific variants and the histopathology findings.…”

Section: Nucleotide Variability and Risk Of Cervical Neoplasiamentioning

confidence: 88%

“…Furthermore, we observed that the HPV-18 prototype sequence was more active than the HPV-16 prototype. It has also been reported that a commonly detected substitution overlapping the Sp-1 binding site at the 3' end of the LCR enhances the transcriptional activity from the P105 HPV-18 main early promoter, since the binding of the Sp-1 protein to this sequence is also increased (31).…”

Section: Nucleotide Variability and Oncogenic Potentialmentioning

confidence: 99%

Epidemiological and functional implications of molecular variants of human papillomavirus

Sichero¹,

Villa²

2006

Braz J Med Biol Res

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Human papillomavirus genomes are classified into molecular variants when they present more than 98% of similarity to the prototype sequence within the L1 gene. Comparative nucleotide sequence analyses of these viruses have elucidated some features of their phylogenetic relationship. In addition, human papillomavirus intratype variability has also been used as an important tool in epidemiological studies of viral transmission, persistence and progression to clinically relevant cervical lesions. Until the present, little has been published concerning the functional significance of molecular variants. It has been shown that nucleotide variability within the long control region leads to differences in the binding affinity of some cellular transcriptional factors and to the enhancement of the expression of E6 and E7 oncogenes. Furthermore, in vivo and in vitro studies revealed differences in E6 and E7 biochemical and biological properties among molecular variants. Nevertheless, further correlation with additional functional information is needed to evaluate the significance of genome intratypic variability. These results are also important for the development of vaccines and to determine the extent to which immunization with L1 virus-like particles of one variant could induce antibodies that cross-neutralize other variants. Key words Papillomavirus heterogeneityThe first evidence for the existence of different human papillomavirus (HPV) types was obtained in the early 1970's when it was observed that mRNA purified from plantar warts hybridized with DNA purified from other plantar warts but not from warts at other sites, including anogenital ones. In the following years, the genetic heterogeneity of HPV was confirmed by restriction fragment length polymorphism analysis and this was followed by an extensive and clear definition of HPV types based on DNA sequencing of different genes and the long control region (LCR) (1).HPV types are defined as a viral genome with an L1 late gene sequence that is at least 10% dissimilar from that of any other type. To date more than 120 different HPV genotypes associated with infections in humans have been described. In addition, the Papillomavirus Nomenclature Committee has established that HPV genomes be classified into molecular variants when they present more than 98% of similarity to the prototype

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“…Multiple YY1 binding sites have been identified in the HPV18 upstream regulatory region (URR), of which the promoter-proximal site plays a functional role (22). While the majority of the HPV18 cancer isolates carry mutations or deletions in YY1 binding sites which confer transcriptional activation of the promoter (45)(46)(47)(48), the significance of the promoter proximal YY1 site as a conditional activating site has been recently reported in HeLa cells. When another sequence 130 bp 5' upstream relative to the YY1 site termed the 'switch region' is present in the HPV18 URR, the promoter proximal YY1 site serves as a positive promoter regulatory element.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of VEGF and TGF-β1 mRNA in Pap smears correlates with progression of cervical intraepithelial neoplasia to cancer: Implication of YY1 in cervical tumorigenesis and HPV infection

Baritaki

Sifakis²,

Huerta-Yépez³

et al. 2007

Int J Oncol

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Abstract. The screening of neo-angiogenesis related gene expression has uncovered many disrupted molecular pathways which may significantly confer to malignant transformation of various cell types including cervical cells. The objective of the present study was to delineate whether changes in certain gene expression profiles during the malignant conversion of the uterine cervix can be potentially used to predict the clinical course and outcome of the cervical pathology. Total RNA was isolated from Pap smears obtained from healthy females or patients diagnosed with low-grade squamous cervical intraepithelial lesions (LG-SIL), high-grade (HG)-SIL or cervical carcinoma. VEGF, TGF-ß1 and YY1 mRNA expression levels were assessed by QRT-PCR. Confirmation of YY1 protein discrepancy among cervical tissues of different histopathology was performed by immunohistochemistry. All tested genes showed statistically significant expression variations among the indicated groups. VEGF and TGF-ß1 mRNA overexpression was found to be associated with progression from low-grade to high-grade cervical intraepithelial neoplasia (CIN), while YY1 showed constitutively elevated transcript levels in CIN and cervical cancer compared to controls. At the protein level YY1 was also overexpressed in HG-SIL and cancer tissues compared to LG-SIL. Both YY1 transcript and protein overexpression were associated with HPV18-or HPV16-infected samples. Spearman analysis revealed a co-expression pattern for VEGF and TGF-ß1 mRNAs in normal cervix and LG-SIL; however, YY1 expression correlated negatively with VEGF and TGF-ß1 transcript levels upon the onset of the cervical neoplastic transformation. Our findings provide for the first time evidence for the implication of YY1 in uterine cervix carcinogenesis and suggest that VEGF, TGF-ß1 and YY1 could be useful biomarkers of cervical malignant transformation as well as potential targets for therapeutic approaches.

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Point mutations in SP1 motifs in the upstream regulatory region of human papillomavirus type 18 isolates from cervical cancers increase promoter activity.

Cited by 23 publications

References 19 publications

The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters

The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters

Epidemiological and functional implications of molecular variants of human papillomavirus

Overexpression of VEGF and TGF-β1 mRNA in Pap smears correlates with progression of cervical intraepithelial neoplasia to cancer: Implication of YY1 in cervical tumorigenesis and HPV infection

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