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Hsp90 inhibition attenuates LPS‐mediated NF‐κB‐dependent gene activation by preventing the de‐acetylation and maintaining the DNA binding of acetyl‐histone H3(K9) in human lung microvascular endothelial cells (HLMVEC)
Author(s) -
Thangjam Gagan Singh,
Joshi Atul Dattatray,
Barabutis Nektarios,
Dimitropoulou Christiana,
Shaw Mary Cherian,
Patel Vijay,
Fulton David,
Catravas John D
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.724.15
Subject(s) - histone h3 , acetylation , histone , p38 mitogen activated protein kinases , reporter gene , microbiology and biotechnology , transcription factor , promoter , phosphorylation , transcription (linguistics) , gene expression , chemistry , regulation of gene expression , nf κb , biology , mapk/erk pathway , gene , signal transduction , biochemistry , linguistics , philosophy
Heat shock protein 90 (hsp90) regulates the stability and function of pro‐inflammatory intermediates, including the inflammatory transcription actor, NF‐κB. NF‐κB dependent gene activation requires the displacement of constitutively acetylated histone‐ H3(Lys9) from NF‐κB responsive promoters by, and subsequent binding of, p65. We studied the role of hsp90 in the regulation of histone‐H3/DNA interaction and its effect on NF‐κB gene activation in HLMVEC. Exposure of HLMVEC to LPS (1 EU/ml for 1h) downregulated acetyl‐H3(Lys9) levels and binding to the NF‐κB‐regulated IKBα promoter. This was associated with increased IKBα mRNA expression, increased p65 DNA binding and NF‐κB reporter gene activation. These steps were blocked by treatment with the hsp90 inhibitor, 17‐AAG (5 μg/ml). Since p38 MAPK also enhances transcription by inducing histone‐H3(Ser10) phosphorylation, we also studied its regulation by hsp90. Both 17‐ AAG and the p38 MAPK inhibitor, SB203580 (10 μM), prevented H3(Ser10) phosphorylation and NF‐κB reporter gene activation by LPS. However, unlike 17‐AAG, SB203580 did not block p65 binding to the IKBα promoter. We conclude that hsp90 inhibition blocks LPS‐mediated NF‐κB gene activation by preventing acetyl‐H3(Lys9) downregulation and thus attenuating p65 binding to relevant DNA elements, via a p38 MAPK‐independent mechanism. (Supported by HL093460).