The p38 MAPK pathway promotes c-fos mRNA decay

MARÍA SOL DEGESE; TAMARA TANOS; JULIAN NAIPAUER; PAULA RABINOVICH; J. SILVIO GUTKIND; OMAR COSO

Los Cocos

Simposio; First Spring Symposium in Signal Transduction and molecular medicine; 2010

Cells respond to extracellular stimuli changing its metabolism, citoskeletal structures and the protein repertoire. MAPK pathways constitute key regulatory elements for changes in the gene expression pattern. The expression levels of early responsive genes of the AP-1 family, as c-fos, peak shortly after cells are stimulated with growth factors and sharply decrease afterwards. Mechanisms that control rapid induction of c-fos promoter activity have been widely studied. On the other hand, much less is known regarding signaling pathways and c-fos mRNA decay. Proteins known as AUBPs bind to specific motifs (AREs) in the 3’UTR region of mRNAs changing its stability. We observed that the stabilizing AUBP HuR binds to the c-fos ARE following a time course after growth factor stimulation, that peaks consistently with a maximum in the amount of c-fos mRNA present. 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 pathway promotes HuR disassociation from the ARE. Our experiments support that while the ERK1/2 pathway is mainly responsible for c-fos promoter induction, activation of the p38 pathway inactivates the stabilizing effect of HuR and restores low levels of c-fos expression.