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NFX1 plays a role in human papillomavirus type 16 E6 activation of NFkappaB activity.

ABSTRACT: High-risk human papillomavirus (HR HPV) requires differentiating epithelial cells to continue to divide in order to replicate the viral DNA. To achieve this, HPV perturbs several regulatory pathways, including cellular apoptosis and senescence signals. HPV E6 has been identified as a regulator of the NF?B signaling pathway, a pathway important in many cellular processes, as well as regulation of virus-host cell interactions. We report here that NFX1-91, an endogenously expressed transcriptional regulator of human telomerase reverse transcriptase (hTERT) that is targeted by HPV type 16 (HPV16) E6/E6-associated protein (E6AP) for degradation, is also critical for regulation of the NF?B pathway by HPV16 E6. Microarray analysis revealed induction of NF?B-responsive genes and reduction of NF?B inhibitors with knockdown of NFX1-91. Knockdown of NFX1-91 induced downregulation of p105, an NF?B inhibitor in both primary human foreskin keratinocytes (HFKs) and HCT116 cells. Chromatin immunoprecipitation assays further confirmed that NFX1-91 bound to the p105 promoter and upregulated its expression. Similarly, in HPV16 E6-positive cells, reduction of p105 expression was observed, paralleling knockdown of NFX1-91 expression. Overall, our data suggest a mechanism for HPV16 E6 activation of the NF?B pathway through NFX1-91. Also, it provides evidence that NFX1-91 can function as a dual regulator, not only a transcriptional repressor, but also a transcriptional activator, when bound to DNA.

SUBMITTER: Xu M

PROVIDER: S-EPMC2953198 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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NFX1 plays a role in human papillomavirus type 16 E6 activation of NFkappaB activity.

Xu Mei M Katzenellenbogen Rachel A RA Grandori Carla C Galloway Denise A DA

Journal of virology 20100825 21

High-risk human papillomavirus (HR HPV) requires differentiating epithelial cells to continue to divide in order to replicate the viral DNA. To achieve this, HPV perturbs several regulatory pathways, including cellular apoptosis and senescence signals. HPV E6 has been identified as a regulator of the NFκB signaling pathway, a pathway important in many cellular processes, as well as regulation of virus-host cell interactions. We report here that NFX1-91, an endogenously expressed transcriptional ...[more]

PMID: 20739528

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Project description:PurposeHigh-risk human papillomaviruses (HR HPV) cause cervical cancer, and in these cancers, HPV type 16 is the most common HR type. The HR viral oncogenes E6 and E7 partner with cellular proteins to drive cancer and modulate immune pathways; previously, we demonstrated in keratinocytes that HPV 16 E6 and high expression of the endogenous host protein partner NFX1-123 led to the increased expression of multiple genes, including Notch1, secretory leukocyte peptidase inhibitor (SLPI), and retinoic acid early transcript 1G (RAET1G). The present study was conducted to determine if NFX1-123 was highly expressed in cervical cancer and if genes increased by NFX1-123 and 16E6 in keratinocytes were also increased in cervical cancers.Materials and methodsThe Cancer Genome Atlas (TCGA) database and The Human Protein Atlas database were used to compare relative mRNA and protein gene expression, respectively, in the normal cervix and cervical cancers. Formalin-fixed paraffin-embedded (FFPE) normal cervix and HPV 16 positive cervical cancer samples were analyzed for relative protein expression by immunohistochemical staining. Protein expression of a subset of regulated genes was quantified by Western blot of HPV positive and negative cell lines.ResultsImmunohistochemical staining of HPV 16 positive cervical dysplasias and cancers revealed high NFX1-123, Ki67, and Notch1 expression. NFX1 and NFX1L1 mRNA levels were increased in cervical cancers compared to normal cervix in the TCGA database. Fourteen genes previously identified as upregulated in keratinocytes with 16E6 and overexpressed NFX1-123 also had high mRNA expression and selected genes had high protein expression in cervical cancers and cell lines.ConclusionIn cervical cancer, NFX1-123 is highly expressed, and 16E6 and NFX1-123 together alter the expression of a wide set of genes. The involvement of these genes in cell proliferation, differentiation, invasion, and metastasis provides further insight into potential ways that HR HPVs promote cancer initiation and maintenance.

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NFX1 plays a role in human papillomavirus type 16 E6 activation of NFkappaB activity.

Publications

NFX1 plays a role in human papillomavirus type 16 E6 activation of NFkappaB activity.

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