Staab, Julia F.

[["dc.bibliographiccitation.artnumber","22"],["dc.bibliographiccitation.journal","BMC Cell Biology"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Koch, Verena"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Ruppert, Volker"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T09:07:06Z"],["dc.date.available","2018-11-07T09:07:06Z"],["dc.date.issued","2012"],["dc.description.abstract","Background: In interferon-gamma-stimulated cells, the dimeric transcription factor STAT1 (signal transducer and activator of transcription 1) recognizes semi-palindromic motifs in the promoter regions of cytokine-driven target genes termed GAS (gamma-activated sites). However, the molecular steps that facilitate GAS binding and the subsequent liberation of STAT1 homodimers from these promoter elements are not well understood. Results: Using a mutational approach, we identified two critical glutamyl residues within the DNA-binding domain adjacent to the phosphodiester backbone of DNA which efficiently release phospho-STAT1 from DNA. The release of STAT1 dimers from DNA enhances transcriptional activity on both interferon-driven reporter and endogenous target genes. A substitution of either of the two glutamic acid residues broadens the repertoire of putative binding sites on DNA and enhances binding affinity to GAS sites. However, despite elevated levels of tyrosine phosphorylation and a prolonged nuclear accumulation period, the STAT1 DNA-binding mutants show a significantly reduced transcriptional activity upon stimulation of cells with interferon-gamma. This reduced transcriptional response may be explained by the deposition of oligomerized STAT1 molecules outside GAS sites. Conclusions: Thus, two negatively charged amino acid residues in the DNA-binding domain are engaged in the liberation of STAT1 from DNA, resulting in a high dissociation rate from non-GAS sites as a key feature of STAT1 signal transduction, which positively regulates cytokine-dependent gene expression probably by preventing retention at transcriptionally inert sites."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2012"],["dc.identifier.doi","10.1186/1471-2121-13-22"],["dc.identifier.isi","000311905000001"],["dc.identifier.pmid","22920460"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8363"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/25711"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1471-2121"],["dc.rights","CC BY 2.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.0"],["dc.title","Two glutamic acid residues in the DNA-binding domain are engaged in the release of STAT1 dimers from DNA"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","596"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Molecular Immunology"],["dc.bibliographiccitation.lastpage","606"],["dc.bibliographiccitation.volume","67"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Riebeling, Theresa"],["dc.contributor.author","Koch, Verena"],["dc.contributor.author","Herrmann-Lingen, Christoph"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T09:51:03Z"],["dc.date.available","2018-11-07T09:51:03Z"],["dc.date.issued","2015"],["dc.description.abstract","Defective cooperative DNA binding of STAT1 (signal transducer and activator of transcription 1) transcription factor has impact on interferon-gamma(IFN gamma)-regulated transcriptional responses. In this study, we generated N-terminal gain-of-function mutants of this protein which exhibited hyperactive cooperativity and assessed their functional consequences on gene expression. Our data show that four negatively charged, surface-exposed amino acid residues in the N-terminal domain dimer are engaged in the disassembly of tyrosine-phosphorylated tetrameric complexes on DNA and prevent the occurrence of higher-order STAT1 oligomers on low-affinity DNA binding sites. Owing to their improved tetramer stability, the N-terminal mutants showed relaxed sequence requirements for the binding to DNA as compared to the wild-type protein. Similarly to a STAT1 mutant with impaired tetramerization, the N-terminal gain-of-function mutants showed elevated tyrosine-phosphorylation levels and prolonged nuclear accumulation upon stimulation of cells with IFN gamma. However, in contrast to the global impairment of IFN gamma signalling in tetramerization-deficient mutants, the transcriptional consequences of the N-terminal gain-of-function mutants are rather distinct and affect gene expression locally in a promoter-specific manner. Thus, we conclude that the STAT1 N-domain acts as a double-edged sword: while one interface is crucial for the formation of tetrameric complexes on IFN gamma-regulated promoters, the opposite interface harbours an inhibitory mechanism that limits the accumulation of higher-order oligomers simply by disrupting cooperative DNA binding. (C) 2015 Published by Elsevier Ltd."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG) [1816]; DFG"],["dc.identifier.doi","10.1016/j.molimm.2015.07.015"],["dc.identifier.isi","000361922400045"],["dc.identifier.pmid","26275341"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35836"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","0161-5890"],["dc.title","The two interfaces of the STAT1 N-terminus exhibit opposite functions in IFN gamma-regulated gene expression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Psychosomatic Medicine"],["dc.bibliographiccitation.volume","75"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Koch, Verena"],["dc.contributor.author","Herrmann-Lingen, Christoph"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T09:26:09Z"],["dc.date.available","2018-11-07T09:26:09Z"],["dc.date.issued","2013"],["dc.format.extent","A81"],["dc.identifier.isi","000330467400256"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/30233"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Lippincott Williams & Wilkins"],["dc.publisher.place","Philadelphia"],["dc.relation.conference","71st Annual Scientific Meeting of the American-Psychosomatic-Society"],["dc.relation.eventlocation","Miami, FL"],["dc.relation.issn","1534-7796"],["dc.relation.issn","0033-3174"],["dc.title","HIGH-AFFINITY DNA-BINDING MUTANTS OF THE STAT1 TRANSCRIPTION FACTOR USED AS TOOLS IN THE STUDY OF INTERFERON-INDUCED DEPRESSION"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]