title: Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells.
abstract: The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-κB-mediated transcription is the major basis for their anti-inflammatory properties. While the molecular mechanisms underlying this effect are not clear, they appear to be distinct in human endothelial cells. We now show for the first time that type 2 sirtuin (Sirt-2) histone deacetylase binds human NF-κB target gene promoter and prevents the recruitment of NF-κB proteins and subsequent assembly of RNA polymerase II complex in human lung microvascular endothelial cells. Hsp90 inhibitors stabilize the Sirt-2/promoter interaction and impose a "transcriptional block," which is reversed by either inhibition or downregulation of Sirt-2 protein expression. Furthermore, this process is independent of NF-κB (p65) Lysine 310 deacetylation, suggesting that it is distinct from known Sirt-2-dependent mechanisms. We demonstrate that Sirt-2 is recruited to NF-κB target gene promoter via interaction with core histones. Upon inflammatory challenge, chromatin remodeling and core histone H3 displacement from the promoter region removes Sirt-2 and allows NF-κB/coactivator recruitment essential for RNA Pol II-dependent mRNA induction. This novel mechanism may have important implications in pulmonary inflammation.
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia;
authors.forename: Gagan S
authors.initials: GS
authors.lastname: Thangjam
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia;
authors.forename: Charalampos
authors.initials: C
authors.lastname: Birmpas
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia;
authors.forename: Nektarios
authors.initials: N
authors.lastname: Barabutis
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia;
authors.forename: Betsy W
authors.initials: BW
authors.lastname: Gregory
authors.affiliation: Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, Virginia;
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Clemens
authors.affiliation: Department of Surgery, Eastern Virginia Medical School, Norfolk, Virginia;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Newton
authors.affiliation: Vascular Biology Center, Augusta University, Augusta, Georgia; and.
authors.forename: David
authors.initials: D
authors.lastname: Fulton
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia; School of Medical Diagnostic and Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, Virginia jcatrava@odu.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Catravas
mesh_terms: D000107:Acetylation; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000276:immunology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000276:immunology / Q000473:pathology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D016227:Benzoquinones; C508606:CXCL8 protein, human; D018841:HSP90 Heat-Shock Proteins; D016209:Interleukin-8; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; C498143:RELA protein, human; D051996:Transcription Factor RelA; C112765:tanespimycin; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: Hsp90; NF-κB; Sirt-2; histone h3; human lung endothelial cells