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Molecular and Cellular Biology, August 2005, p. 6454-6463, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6454-6463.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Convergent Actions of I{kappa}B Kinase ß and Protein Kinase C{delta} Modulate mRNA Stability through Phosphorylation of 14-3-3ß Complexed with Tristetraprolin{dagger}

Sonja I. Gringhuis,* Juan Jesús García-Vallejo, Bert van het Hof, and Willem van Dijk

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MC Amsterdam, The Netherlands

Received 26 November 2004/ Returned for modification 22 December 2004/ Accepted 4 May 2005

Regulation of gene expression at the level of mRNA stability is a major topic of research; however, knowledge about the regulatory mechanisms affecting the binding and function of AU-rich element (ARE)-binding proteins (AUBPs) in response to extracellular signals is minimal. The ß1,4-galactosyltransferase 1 (ß4GalT1) gene enabled us to study the mechanisms involved in binding of tristetraprolin (TTP) as the stability of its mRNA is regulated solely through one ARE bound by TTP in resting human umbilical vein endothelial cells. Here, we provide evidence that the complex formation of TTP with 14-3-3ß is required to bind ß4GalT1 mRNA and promote its decay. Furthermore, upon tumor necrosis factor alpha stimulation, the activation of both I{kappa}ß kinase and protein kinase C{delta} is involved in the phosphorylation of 14-3-3ß on two serine residues, paralleled by release of binding of TTP and 14-3-3ß from ß4GalT1 mRNA, nuclear sequestration of TTP, and ß4GalT1 mRNA stabilization. Thus, a key mechanism regulating mRNA binding and function of the destabilizing AUBP TTP involves the phosphorylation status of 14-3-3ß.

* Corresponding author. Mailing address: Department of Molecular Cell Biology and Immunology, VU Medical Center, P.O. Box 7057, 1007 MC Amsterdam, The Netherlands. Phone: 31 20 444 8156. Fax: 31 20 444 8081. E-mail: si.gringhuis{at}vumc.nl.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 6454-6463, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6454-6463.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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