An interplay between the p38 MAPK pathway and AUBPs regulate c-fos mRNA stability during mitogenic stimulation

MAPK pathways constitute key regulatory elements linking extracellular stimuli to nuclear gene expression. Immediate-early responsive genes of the AP-1 family, as fos, achieve peak expression levels shortly after cells are stimulated with growth factors, and sharply decrease thereafter. Several AU-rich binding proteins (AUBPs), including HuR and KSRP, bind to a fos ARE element present in the 3’UTR region of fos mRNA regulating its stability by a still poorly defined mechanism. We show here that while HuR binds and stabilizes transcribed reporter mRNAs bearing the fos 3’UTR, KSRP counteracts this effect. Furthermore, we found that fos mRNA stability and HuR phosphorylation status are dependent on the activity of p38 MAPK in both epithelial cells and fibroblasts upon proliferative stimulation. Analyzing PPI (protein-protein interaction) networks, we performed a thorough query of interacting proteins for p38 MAPKs, HuR and other AUBPs upon growth factor stimulation. This revealed novel HuR interactors, including inhibitors to PP2A activity. Over-expression of two of these interactors, pp32 and APRIL and pharmacological inhibition of PP2A stabilized a fos reporter mRNA. Our results indicate that p38 MAPK regulates fos mRNA decay by affecting the state of phosphorylation of HuR while controlling, yet to be fully elucidated, protein phosphatase regulatory networks.

Source: BJ Signal - January 14, 2015 Category: Biochemistry Authors: M Sol Degese, T Tanos, J Naipauer, T Gringerich, D Chiappe, P Echeverria, J LaMarre, J Silvio Gutkind, O Adrian Coso Tags: BJ Signal Source Type: research