Convergent actions of I kappa B kinase beta and protein kinase C delta modulate mRNA stability through phosphorylation of 14-3-3 beta 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 beta1,4-galactosyltransferase 1 (beta4GalT1) 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 14-3-3beta is required to bind beta4GalT1 mRNA and promote its decay. Furthermore, upon tumor necrosis factor alpha stimulation, the activation of both Ikappabeta kinase and protein kinase Cdelta is involved in the phosphorylation of 14-3-3beta on two serine residues, paralleled by release of binding of TTP and 14-3-3beta from beta4GalT1 mRNA, nuclear sequestration of TTP, and beta4GalT1 mRNA stabilization. Thus, a key mechanism regulating mRNA binding and function of the destabilizing AUBP TTP involves the phosphorylation status of 14-3-3beta.
Gringhuis
Sonja I
SI
Department of Molecular Cell Biology and Immunology, VU Medical Center, P.O. Box 7057, 1007 MC Amsterdam, The Netherlands. si.gringhuis@vumc.nl
García-Vallejo
Juan Jesús
JJ
van Het Hof
Bert
B
van Dijk
Willem
W
D048948:14-3-3 Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D017874:Immediate-Early Proteins / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins / Q000201:enzymology
D048948:14-3-3 Proteins; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; D012694:Serine; D005700:Galactosyltransferases; C119701:beta-1,4-galactosyltransferase I; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta