ZNF395 (HDBP2 /PBF) is a Target Gene of Hif-1α

Jordanovski, Darko; Herwartz, Christine; Steger, Gertrud

doi:10.5772/30659

Cited by 4 publications

(6 citation statements)

References 22 publications

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“…We visualized the impact of ZNF395 on the expression of these ISGs in the keratinocyte cell line RTS3b in which we modulated the level of ZNF395 over a wide range by siRNA-mediated suppression and by Dox-induced overexpression. The functional relevance of the contribution of ZNF395 to the IFN α -mediated control of specific well characterized antiviral ISGs, we have identified here, is supported by several reports correlating reduced ZNF395 expression in patient in the context of an infection with HIV1, CMV, and EBV [29–31]. Our results suggest that ZNF395 plays an important role in the modulation of the antiviral innate immune response.…”

Section: Discussionsupporting

confidence: 87%

ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes

Schroeder

Herwartz

Jordanovski

et al. 2017

Mediators of Inflammation

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Activation of the interferon (IFN) pathway in response to infection with pathogens results in the induction of IFN-stimulated genes (ISGs) including proinflammatory cytokines, which mount the proper antiviral immune response. However, aberrant expression of these genes is pathogenic to the host. In addition to IFN-induced transcription factors non-IFN-regulated factors contribute to the transcriptional control of ISGs. Here, we show by genome wide expression analysis, siRNA-mediated suppression and Doxycycline-induced overexpression that the cellular transcription factor ZNF395 activates a subset of ISGs including the chemokines CXCL10 and CXCL11 in keratinocytes. We found that ZNF395 acts independently of IFN but enhances the IFN-induced expression of CXCL10 and CXCL11. Luciferase reporter assays revealed a requirement of intact NFκB-binding sites for ZNF395 to stimulate the CXCL10 promoter. The transcriptional activation of CXCL10 and CXCL11 by ZNF395 was abolished after inhibition of IKK by BMS-345541, which increased the stability of ZNF395. ZNF395 encodes at least two motifs that mediate the enhanced degradation of ZNF395 in response to IKK activation. Thus, IKK is required for ZNF395-mediated activation of transcription and enhances its turn-over to keep the activity of ZNF395 low. Our results support a previously unrecognized role of ZNF395 in the innate immune response and inflammation.

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Section: Discussionsupporting

confidence: 87%

ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes

Schroeder

Herwartz

Jordanovski

et al. 2017

Mediators of Inflammation

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“…The PHD inhibitor dimethyloxalylglycine (DMOG) leads to the stabilization of HIF-1 α and results in increased amounts of ZNF395 independent of the O 2 deficiency [ 9 , 22 ]. To confirm the effect of ZNF395 on the production of IL-6 and IL-8, we treated siZNF395 and siControl transfected U87-MG cells with DMOG for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

“…The notion that ZNF395 is a target gene of HIF-1 α is in line with a CHIP-on-CHIP experiment that revealed the binding of both HIF-1 α and HIF-2 α to two DNA segments which are located several kb upstream of the ORF of ZNF395, respectively [ 35 ]. In correlation, the PHD inhibitor DMOG induced the expression of ZNF395 [ 9 , 22 , 23 , 31 , 36 ]. An upregulation of ZNF395 after hypoxia was described for additional glioblastoma-derived cell lines [ 8 , 9 ] and most importantly an increased expression of ZNF395 as a part of a hypoxic response was observed in human solid tumors such as GBMs [ 8 ] and neuroblastomas [ 13 ] implying that also in these in vivo situations ZNF395 enhances the hypoxic induction of these proinflammatory factors and may thus significantly contribute to disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…We identified ZNF395 by its ability to repress transcription of some papillomaviruses [ 19 , 20 ]. The protein was also found to inhibit the Huntington disease (HD) gene promoter [ 21 , 22 ]. We have shown previously that ZNF395 can act as repressor or activator of transcription depending on the promoter and the cellular environment.…”

Section: Introductionmentioning

confidence: 99%

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The Transcription Factor ZNF395 Is Required for the Maximal Hypoxic Induction of Proinflammatory Cytokines in U87‐MG Cells

Herwartz

Castillo-Juárez

Schröder

et al. 2015

Mediators of Inflammation

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Hypoxia activates the expression of proangiogenic and survival promoting factors as well as proinflammatory cytokines that support tissue inflammation. Hypoxia and inflammation are associated with tumor progression. The identification of the factors participating in the hypoxia associated inflammation is essential to develop strategies to control tumor hypoxia. The transcription factor ZNF395 was found to be overexpressed in various tumors including glioblastomas particularly in the network of a hypoxic response pointing to a functional role of ZNF395. On the other hand, ZNF395 was suggested to have tumor suppressor activities which may rely on its repression of proinflammatory factors. To address these conflictive observations, we investigated the role of ZNF395 in the expression of proinflammatory cytokines in the astrocytoma cell line U87-MG under hypoxia. We show that ZNF395 is a target gene of the hypoxia inducible factor HIF-1α. By gene expression analysis, RT-PCR and ELISA, we demonstrated that the siRNA-mediated suppression of ZNF395 impairs the hypoxic induction of IL-1β, IL-6, IL-8, and LIF in U87-MG cells. At ambient oxygen concentrations, ZNF395 had no enhancing effect, indicating that this transcriptional activation by ZNF395 is restricted to hypoxic conditions. Our results suggest that ZNF395 contributes to hypoxia associated inflammation by superactivating proinflammatory cytokines.

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“…ZNF395 was characterized as a nucleo-cytoplasmic shuttling protein [22,23]. The overexpression of ZNF395 induced cell death [24] and repressed both the HD-promoter and the human PV type 8 (HPV8) promoter, which depended on DNA binding of ZNF395 and on targeting the SIN3/HDAC1/2 complex [25,26]. We were interested in identifying other target genes of ZNF395 and understanding the control of its transcriptional activity.…”

Section: Introductionmentioning

confidence: 99%

The Hypoxia-Inducible Transcription Factor ZNF395 Is Controlled by IĸB Kinase-Signaling and Activates Genes Involved in the Innate Immune Response and Cancer

et al. 2013

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Activation of the hypoxia inducible transcription factor HIF and the NF-ĸB pathway promotes inflammation-mediated tumor progression. The cellular transcription factor ZNF395 has repeatedly been found overexpressed in various human cancers, particularly in response to hypoxia, implying a functional relevance. To understand the biological activity of ZNF395, we identified target genes of ZNF395 through a genome-wide expression screen. Induced ZNF395 expression led to the upregulation of genes known to play a role in cancer as well as a subset of interferon (IFN)-stimulated genes (ISG) involved in antiviral responses such as IFIT1/ISG56, IFI44 and IFI16. In cells that lack ZNF395, the IFN-α-mediated stimulation of these factors was impaired, demonstrating that ZNF395 is required for the full induction of these antiviral genes. Transient transfections revealed that ZNF395-mediated activation of the IFIT1/ISG56 promoter depends on the two IFN-stimulated response elements within the promoter and on the DNA-binding domain of ZNF395, a so-called C-clamp. We also show that IĸBα kinase (IKK)-signaling is necessary to allow ZNF395 to activate transcription and simultaneously enhances its proteolytic degradation. Thus, ZNF395 becomes activated at the level of protein modification by IKK. Moreover, we confirm that the expression of ZNF395 is induced by hypoxia. Our results characterize ZNF395 as a novel factor that contributes to the maximal stimulation of a subset of ISGs. This transcriptional activity depends on IKK signaling further supporting a role of ZNF395 in the innate immune response. Given these results it is possible that under hypoxic conditions, elevated levels of ZNF395 may support inflammation and cancer progression by activating the target genes involved in the innate immune response and cancer.

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ZNF395 (HDBP2 /PBF) is a Target Gene of Hif-1α

Cited by 4 publications

References 22 publications

ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes

ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes

The Transcription Factor ZNF395 Is Required for the Maximal Hypoxic Induction of Proinflammatory Cytokines in U87‐MG Cells

The Hypoxia-Inducible Transcription Factor ZNF395 Is Controlled by IĸB Kinase-Signaling and Activates Genes Involved in the Innate Immune Response and Cancer

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