Universität zu Köln

Jordanovski, Darko, Herwartz, Christine, Pawlowski, Anna, Taute, Stefanie, Frommolt, Peter ORCID: 0000-0002-1966-8014 and Steger, Gertrud (2013). The Hypoxia-Inducible Transcription Factor ZNF395 Is Controlled by I kappa B Kinase-Signaling and Activates Genes Involved in the Innate Immune Response and Cancer. PLoS One, 8 (9). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Activation of the hypoxia inducible transcription factor HIF and the NF-kappa B 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-alpha-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 I kappa B alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jordanovski, Darko UNSPECIFIED UNSPECIFIED UNSPECIFIED Herwartz, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Pawlowski, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Taute, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Frommolt, Peter UNSPECIFIED orcid.org/0000-0002-1966-8014 UNSPECIFIED Steger, Gertrud UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-475721
DOI:	10.1371/journal.pone.0074911
Journal or Publication Title:	PLoS One
Volume:	8
Number:	9
Date:	2013
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PAPILLOMAVIRUS BINDING-FACTOR; CELL-LINE; EXPRESSION; PROTEIN; PHOSPHORYLATION; ALPHA; BETA; INHIBITION; TARGET; FAMILY Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47572