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J. Biol. Chem., Vol. 280, Issue 18, 18411-18417, May 6, 2005

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Inhibition of p90 Ribosomal S6 Kinase-mediated CCAAT/Enhancer-binding Protein Activation and Cyclooxygenase-2 Expression by Salicylate^*

Katarzyna A. Cieslik, Ying Zhu, Mikhail Shtivelband, and Kenneth K. Wu¶

From the Vascular Biology Research Center and Division of Hematology, Brown Foundation Institute of Molecular Medicine and Medical School, The University of Texas Health Science Center and Texas Heart Institute, Houston, Texas 77030-1503

We have previously shown that salicylate at a pharmacological concentration suppresses CCAAT/enhancer-binding protein (C/EBP) binding, thereby reducing cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase expression (Saunders, M. A., Sansores-Garcia, L., Gilroy, D. W., and Wu, K. K. (2001) J. Biol. Chem. 276, 18897-18904; Cieslik, K., Zhu, Y., and Wu, K. K. (2002) J. Biol. Chem. 277, 49304-49310). We postulated that salicylate targets a kinase that phosphorylates and activates C/EBP. Here we report the identification of p90 ribosomal S6 kinase (RSK) as a target of salicylate. Salicylate inhibited RSK in vivo and blocked the activity of RSK2 purified from cells stimulated by phorbol 12-myristate 13-acetate (PMA). Mutation of the RSK-phosphorylation site (T266A) of C/EBP abrogated PMA-stimulated C/EBP binding activity. RSK activation was required for PMA-induced COX-2 transcriptional activation. Salicylate also inhibited Ras and extracellular signal-regulated kinase (ERK) activation induced by PMA. We conclude that salicylate inhibits C/EBP-mediated COX-2 transcriptional activation by blocking RSK activity and Ras signaling pathway.

Received for publication, August 31, 2004 , and in revised form, January 20, 2005.

^* This work was supported by National Institutes of Health Grants P50 NS-23327 and R01 HL-50675. 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.

Present Address: College of Life Science, Wuhan University, Wuhan, 430072 Hubei, China.

^¶ To whom correspondence should be addressed. Tel.: 713-500-6801; Fax: 713-500-6812; E-mail: Kenneth.K.Wu{at}uth.tmc.edu.

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