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J. Biol. Chem., Vol. 283, Issue 24, 16391-16399, June 13, 2008

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NF-B-dependent Transcriptional Activation in Lung Carcinoma Cells by Farnesol Involves p65/RelA(Ser²⁷⁶) Phosphorylation via the MEK-MSK1 Signaling Pathway^*

From the Cell Biology Section, LRB, Division of Intramural Research, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

In this study, we demonstrate that treatment of human lung adenocarcinoma H460 cells with farnesol induces the expression of a number of immune response and inflammatory genes, including IL-6, CXCL3, IL-1, and COX-2. This response was dependent on the activation of the NF-B signaling pathway. Farnesol treatment reduces the level of IB and induces translocation of p65/RelA to the nucleus, its phosphorylation at Ser²⁷⁶, and transactivation of NF-B-dependent transcription. Moreover, overexpression of IB or treatment with the NF-B inhibitor caffeic acid phenethyl ester greatly diminishes the induction of inflammatory gene expression by farnesol. We provide evidence indicating that the farnesol-induced phosphorylation of p65/RelA at Ser²⁷⁶ is important for optimal transcriptional activity of NF-B. The MEK1/2 inhibitor U0126 and knockdown of MEK1/2 expression with small interfering RNAs effectively blocked the phosphorylation of p65/RelA(Ser²⁷⁶) but not that of Ser⁵³⁶, suggesting that this phosphorylation is dependent on the activation of the MEK1/2-ERK1/2 pathway. We further show that inhibition of MSK1, a kinase acting downstream of MEK1/2-ERK1/2, by H89 or knockdown of MSK1 expression also inhibited phosphorylation of p65/RelA(Ser²⁷⁶), suggesting that this phosphorylation is dependent on MSK1. Knockdown of MEK1/2 or MSK1 expression inhibits farnesol-induced expression of CXCL3, IL-1, and COX-2 mRNA. Our results indicate that the induction of inflammatory genes by farnesol is mediated by the activation of the NF-B pathway and involves MEK1/2-ERK1/2-MSK1-dependent phosphorylation of p65/RelA(Ser²⁷⁶). The activation of the NF-B pathway by farnesol might be part of a prosurvival response during farnesol-induced ER stress.

Received for publication, February 5, 2008 , and in revised form, March 28, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health, NIEHS, Intramural Research Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The data discussed in this publication have been deposited in the NCBI Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series Accession number GSE7215 [NCBI GEO] .

¹ To whom correspondence should be addressed: Cell Biology Section, LRB, Division of Intramural Research, NIEHS, National Institutes of Health, 111 T. W. Alexander Dr., Research Triangle Park, North Carolina 27709. Tel.: 919-541-2768; Fax: 919-541-4133; E-mail: jetten{at}niehs.nih.gov.

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