Convergent actions of IκB kinase p and protein kinase Cδ modulate mRNA stability through phosphorylation of 14-3-3β complexed with tristetraprolin

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 beta 1,4-galactosyltransferase 1 (beta 4GalT1) 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 14-3-3 beta is required to bind beta 4GalT1 mRNA and promote its decay. Furthermore, upon tumor necrosis factor alpha stimulation, the activation of both I kappa beta kinase and protein kinase C delta is involved in the phosphorylation of 14-3-3 beta on two serine residues, paralleled by release of binding of TTP and 14-3-3 beta from beta 4GalT1 mRNA, nuclear sequestration of TTP, and beta 4GalT1 mRNA stabilization. Thus, a key mechanism regulating mRNA binding and function of the destabilizing AUBP TTP involves the phosphorylation status of 14-3-3 beta.