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J. Biol. Chem., Vol. 282, Issue 6, 3766-3777, February 9, 2007

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Tristetraprolin (TTP)-14-3-3 Complex Formation Protects TTP from Dephosphorylation by Protein Phosphatase 2a and Stabilizes Tumor Necrosis Factor- mRNA^*

Lei Sun, Georg Stoecklin, Susan Van Way, Vania Hinkovska-Galcheva, Ren-Feng Guo^¶, Paul Anderson, and Thomas Patrick Shanley¹

From the Division of Critical Care, Department of Pediatrics and the ^¶Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 and the Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Tumor necrosis factor (TNF)- is a major cytokine produced by alveolar macrophages in response to pathogen-associated molecular patterns such as lipopolysaccharide. TNF- secretion is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional regulation occurs by modulation of TNF- mRNA stability via the binding of tristetraprolin (TTP) to the adenosine/uridine-rich elements found in the 3'-untranslated region of the TNF- transcript. Phosphorylation plays important roles in modulating mRNA stability, because activation of p38 MAPK by lipopolysaccharide stabilizes TNF- mRNA. We hypothesized that the protein phosphatase 2A (PP2A) regulates this signaling pathway. Our results show that inhibition of PP2A by okadaic acid or small interference RNA significantly enhanced the stability of TNF- mRNA. This result was associated with increased phosphorylation of p38 MAPK and MAPK-activated kinase 2 (MK-2). PP2A inhibition increased TTP phosphorylation and enhanced complex formation with chaperone protein 14-3-3. TTP physically interacted with PP2A in transfected mammalian cells. A functional consequence of TTP-14-3-3 complex formation appeared to be protection of TTP from dephosphorylation by inhibition of the binding of PP2A to phosphorylated TTP. Mutation of the MK-2 phosphorylation sites of TTP did not influence TNF- adenosine/uridine-rich element binding and did not alter the increased TNF- 3'-untranslated region-dependent luciferase activity induced by PP2A-small interference RNA silencing. Our data indicate that, although phosphorylation stabilizes TNF- mRNA, PP2A regulates the mRNA stability by modulating the phosphorylation state of members of the p38/MK-2/TTP pathway.

Received for publication, August 2, 2006 , and in revised form, December 12, 2006.

^* This work was supported by National Institutes of Health Grant 7R01GM066839-03 (to T. P. S.). 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.

¹ To whom correspondence should be addressed: Division of Critical Care, Dept. of Pediatrics, University of Michigan Medical School, 109 Zina Pitcher Place, 4460 Basic Science Research Building, Ann Arbor, MI 48109. Tel.: 734-764-5302; Fax: 734-647-5624; E-mail: tshanley{at}med.umich.edu.

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