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dc.contributor.author Suliman, HB
dc.contributor.author Sweeney, TE
dc.contributor.author Withers, CM
dc.contributor.author Piantadosi, CA
dc.coverage.spatial England
dc.date.accessioned 2011-06-21T17:27:35Z
dc.date.issued 2010-08-01
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20587593
dc.identifier jcs.064089
dc.identifier.citation J Cell Sci, 2010, 123 (Pt 15), pp. 2565 - 2575
dc.identifier.uri http://hdl.handle.net/10161/4185
dc.description.abstract The nuclear respiratory factor-1 (NRF1) gene is activated by lipopolysaccharide (LPS), which might reflect TLR4-mediated mitigation of cellular inflammatory damage via initiation of mitochondrial biogenesis. To test this hypothesis, we examined NRF1 promoter regulation by NFκB, and identified interspecies-conserved κB-responsive promoter and intronic elements in the NRF1 locus. In mice, activation of Nrf1 and its downstream target, Tfam, by Escherichia coli was contingent on NFκB, and in LPS-treated hepatocytes, NFκB served as an NRF1 enhancer element in conjunction with NFκB promoter binding. Unexpectedly, optimal NRF1 promoter activity after LPS also required binding by the energy-state-dependent transcription factor CREB. EMSA and ChIP assays confirmed p65 and CREB binding to the NRF1 promoter and p65 binding to intron 1. Functionality for both transcription factors was validated by gene-knockdown studies. LPS regulation of NRF1 led to mtDNA-encoded gene expression and expansion of mtDNA copy number. In cells expressing plasmid constructs containing the NRF-1 promoter and GFP, LPS-dependent reporter activity was abolished by cis-acting κB-element mutations, and nuclear accumulation of NFκB and CREB demonstrated dependence on mitochondrial H(2)O(2). These findings indicate that TLR4-dependent NFκB and CREB activation co-regulate the NRF1 promoter with NFκB intronic enhancement and redox-regulated nuclear translocation, leading to downstream target-gene expression, and identify NRF-1 as an early-phase component of the host antibacterial defenses.
dc.format.extent 2565 - 2575
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof J Cell Sci
dc.relation.isversionof 10.1242/jcs.064089
dc.subject Animals
dc.subject Chromatin Immunoprecipitation
dc.subject Computational Biology
dc.subject Cyclic AMP Response Element-Binding Protein
dc.subject DNA, Mitochondrial
dc.subject Electrophoretic Mobility Shift Assay
dc.subject Hep G2 Cells
dc.subject Humans
dc.subject Immunoblotting
dc.subject Inflammation
dc.subject Introns
dc.subject Lipopolysaccharides
dc.subject Male
dc.subject Mice
dc.subject Mice, Inbred C57BL
dc.subject Mitochondria
dc.subject NF-kappa B
dc.subject Nitriles
dc.subject Nuclear Respiratory Factor 1
dc.subject Promoter Regions, Genetic
dc.subject Protein Binding
dc.subject Sulfones
dc.title Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-8-1 en_US
duke.description.endpage 2575 en_US
duke.description.issue 15 en_US
duke.description.startpage 2565 en_US
duke.description.volume 123 en_US
dc.relation.journal Journal of cell science en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20587593
pubs.issue Pt 15
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Anesthesiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Pulmonary, Allergy, and Critical Care Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 123
dc.identifier.eissn 1477-9137

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