p38 MAPK pathway regulation of c-fos mRNA decay. Focus on phosphorylation of AUBPs and their association to the ARE region

MARIA SOL DEGESE; TAMARA TANOS; JULIAN NAIPAUER; DIEGO CHIAPPE; J. SILVIO GUTKIND; PABLO ECHEVERRIA; OMAR A. COSO

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Congreso; SISTAM 2012 - The Second South American Spring Symposium in Signal Transduction and Molecular Medicine? (SISTAM2012); 2012

28.- p38 MAPK pathway regulation of c-fos mRNA decay. Focus on phosphorylation of AUBPs and their association to the ARE region Maria Sol Degese1, Tamara Tanos1, Julian Naipauer1, Diego Chiappe2, J. Silvio Gutkind4, Pablo Echeverria3,& Omar A. Coso1. 1Instituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina. 2Proteomics Core Facility, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 3Department of Cellular Biology, University of Geneva, Geneva, Switzerland. 4Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA. MAPK pathways constitute key regulatory elements for changes in the gene expression pattern in living cells. The expression levels of immediate-early responsive genes of the AP-1 family, as c-fos, peak shortly after cells are stimulated with growth factors and sharply decrease afterwards. We found several AU rich binding proteins, also called AUBPs, bound to the c-fos ARE element, including HuR and KSRP. While HuR binds and stabilizes a reporter mRNA bearing the 3?UTR of c-fos, KSRP reverses this stabilization. HuR and KSRP seem to be competing for the same sites of binding in the ARE suggesting they interplay in a possible mechanism of regulation. We also observed that c-fos mRNA stability and the state of phosphorylation of HuR are dependent on p38 MAPK activity. In addition, the p38 MAPK pathway promotes HuR disassociation from the ARE. With the goal of finding the missing link/s between p38 MAPK and the regulation of HuR and ultimately contribute to understand the mechanism of regulation of c-fos mRNA decay, we engaged in a bioinformatics search of putative candidates for filling the gap in the signaling pathway. Analyzing PPI (protein-protein interaction) networks, we performed a thorough query of p38 MAPKs, HuR and 4 other AUBPs interacting proteins. Interestingly, some of HuR interactors are related to PP2A activity. Finally, not only 2 of these interactors, pp32 and APRIL showed stabilizing properties but also the inhibition of PP2A activity prevented the degradation of the c-fos reporter. We propose that p38 MAPK regulates the process of c-fos mRNA decay through this phosphatase related activity.