HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 3, 1938-1947, January 19, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/3/1938    most recent M606080200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ki, S. H. Articles by Kim, S. G. Search for Related Content PubMed PubMed Citation Articles by Ki, S. H. Articles by Kim, S. G. Social Bookmarking                      What's this?

G₁₂ Specifically Regulates COX-2 Induction by Sphingosine 1-Phosphate

ROLE FOR JNK-DEPENDENT UBIQUITINATION AND DEGRADATION OF IB^*

Sung Hwan Ki, Min Jung Choi, Chang Ho Lee, and Sang Geon Kim¹

From the National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea and the Department of Pharmacology and Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul 133-791, Korea

Cyclooxygenase-2 (COX-2) plays a critical role in vasodilatation and local inflammatory responses during platelet aggregation and thrombosis. Sphingosine 1-phosphate (S1P), a sphingolipid released from activated platelets, stimulates COX-2 induction and activates G-protein-coupled receptors coupled to G family members. In this study, we investigated whether G₁₂ family regulates COX-2 induction by S1P and investigated the molecular basis of this COX-2 regulation. Gene knock-out and chemical inhibitor experiments revealed that the S1P induction of COX-2 requires G₁₂ but not G₁₃, G_q, or G_i/o. The specific role of G₁₂ in COX-2 induction by S1P was verified by promoter luciferase assay, G₁₂ transfection, and knockdown experiments. Experiments using siRNAs specifically directed against S1P_1-5 showed that S1P₁, S1P₃, and S1P₅ are necessary for the full activation of COX-2 induction. Gel shift, immunocytochemistry, chromatin immunoprecipitation, and NF-B site mutation analyses revealed the role of NF-Bin COX-2 gene transcription by S1P. G₁₂ deficiency did not affect S1P-mediated IB phosphorylation but abrogated IB ubiquitination and degradation. Moreover, the inhibition of S1P activation of JNK abolished IB ubiquitination. Consistently, JNK transfection restored the ability of S1P to degrade IB during G₁₂ deficiency. S1P injection induced COX-2 in the lungs and livers of mice and increased plasma prostaglandin E₂, and these effects were prevented by G₁₂ deficiency. Our data indicate that, of the G proteins coupled to S1P receptors, G₁₂ specifically regulates NF-B-mediated COX-2 induction by S1P downstream of S1P₁, S1P₃, and S1P₅, in a process mediated by the JNK-dependent ubiquitination and degradation of IB.

Received for publication, June 26, 2006 , and in revised form, October 31, 2006.

^* This study was supported by Korea Health 21 R&D Project Grant A050123 from the Ministry of Health and Welfare, Republic of Korea. 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea. Tel.: 822-880-7840; Fax: 822-872-1795; E-mail: sgk{at}snu.ac.kr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. J. Cho and S. G. Kim A Novel Mitogen-Activated Protein Kinase Phosphatase-1 and Glucocorticoid Receptor (GR) Interacting Protein-1-Dependent Combinatorial Mechanism of Gene Transrepression by GR Mol. Endocrinol., January 1, 2009; 23(1): 86 - 99. [Abstract] [Full Text] [PDF]

				T. Ohama, M. Okada, T. Murata, D. L. Brautigan, M. Hori, and H. Ozaki Sphingosine-1-phosphate enhances IL-1{beta}-induced COX-2 expression in mouse intestinal subepithelial myofibroblasts Am J Physiol Gastrointest Liver Physiol, October 1, 2008; 295(4): G766 - G775. [Abstract] [Full Text] [PDF]

				T. Boutros, E. Chevet, and P. Metrakos Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer Pharmacol. Rev., September 1, 2008; 60(3): 261 - 310. [Abstract] [Full Text] [PDF]

				R. A. Oyesanya, Z. P. Lee, J. Wu, J. Chen, Y. Song, A. Mukherjee, P. Dent, T. Kordula, H. Zhou, and X. Fang Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells FASEB J, August 1, 2008; 22(8): 2639 - 2651. [Abstract] [Full Text] [PDF]

				A. M. Johann, A. Weigert, W. Eberhardt, A.-M. Kuhn, V. Barra, A. von Knethen, J. M. Pfeilschifter, and B. Brune Apoptotic Cell-Derived Sphingosine-1-Phosphate Promotes HuR-Dependent Cyclooxygenase-2 mRNA Stabilization and Protein Expression J. Immunol., January 15, 2008; 180(2): 1239 - 1248. [Abstract] [Full Text] [PDF]

				M. K. Cho, W. D. Kim, S. H. Ki, J.-I. Hwang, S. Choi, C. H. Lee, and S. G. Kim Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor Mol. Cell. Biol., September 1, 2007; 27(17): 6195 - 6208. [Abstract] [Full Text] [PDF]

				V. Yanamadala, H. Negoro, L. Gunaratnam, T. Kong, and B. M. Denker G{alpha}12 Stimulates Apoptosis in Epithelial Cells through JNK1-mediated Bcl-2 Degradation and Up-regulation of I{kappa}B{alpha} J. Biol. Chem., August 17, 2007; 282(33): 24352 - 24363. [Abstract] [Full Text] [PDF]

				M.-S. Kim, S. M. Lee, W. D. Kim, S. H. Ki, A. Moon, C. H. Lee, and S. G. Kim G{alpha}12/13 Basally Regulates p53 through Mdm4 Expression Mol. Cancer Res., May 1, 2007; 5(5): 473 - 484. [Abstract] [Full Text] [PDF]