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Scholz, Carsten C.
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Scholz, Carsten C.
Official Name
Scholz, Carsten C.
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Now showing 1 - 3 of 3
- PublicationRegulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways(National Academy of Sciences, 2013-10)
; ; ; ; ; ; ; ; ; ; ; Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor κB (NF-κB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1β, a major proinflammatory cytokine that regulates NF-κB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1β-induced NF-κB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1β-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1β signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1β-dependent inflammatory signaling.226Scopus© Citations 121 - PublicationREST is a hypoxia-responsive transcriptional repressor(Springer Nature, 2016-08-17)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.290Scopus© Citations 46 - PublicationREST mediates resolution of HIF-dependent gene expression in prolonged hypoxia(Springer Nature, 2015-12-09)
; ; ; ; ; ; ; ; The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1a expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1a mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1a protein response and the suppression of HIF-1a mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1a promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1a mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1a- (but not HIF-2a-) dependent manner. Finally, REST promotes the resolution of HIF-1a protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1a in prolonged hypoxia, thus contributing to the resolution of the HIF-1a response.234Scopus© Citations 49