Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Mitogen- and stress-activated kinase 1 (MSK1) regulates cigarette smoke-induced histone modifications on NF-ýýB-dependent genes.

Authors: Sundar, Isaac K; Chung, Sangwoon; Hwang, Jae-Woong; Lapek Jr, John D; Bulger, Michael; Friedman, Alan E; Yao, Hongwei; Davie, James R; Rahman, Irfan

Published In PLoS One, (2012)

Abstract: Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKýý (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-ýýB RelA/p65 kinase, mediating transcriptional activation of NF-ýýB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-ýýB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-ýýB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-ýýB activation and chromatin modifications, which have implications in pathogenesis of COPD.

PubMed ID: 22312446 Exiting the NIEHS site

MeSH Terms: Acetylation/drug effects; Animals; Cell Line; Enzyme Activation/drug effects; Gene Knockdown Techniques; Histones/metabolism*; Humans; Mice; Phosphorylation/drug effects; Promoter Regions, Genetic/genetics; Ribosomal Protein S6 Kinases, 90-kDa/deficiency; Ribosomal Protein S6 Kinases, 90-kDa/genetics; Ribosomal Protein S6 Kinases, 90-kDa/metabolism*; Smoke/adverse effects; Smoking/genetics; Smoking/metabolism*; Transcription Factor RelA/metabolism*; p300-CBP Transcription Factors/metabolism

Back
to Top