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

DEGESE, MARIA SOL; TANOS, TAMARA; NAIPAUER, JULIAN; GINGERICH, TIM; CHIAPPE, DIEGO; ECHEVERRIA, PABLO; LAMARRE, JONATHAN; GUTKIND, J. SILVIO; COSO, OMAR A.

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

Año: 2015 vol. 467 p. 77 - 90

0264-6021

Mitogen-activated protein kinase (MAPK) pathways constitutekey regulatory elements linking extracellular stimuli to nucleargene expression. Immediate-early responsive genes (IEGs) ofthe activator protein 1 (AP-1) family, such as fos, achievepeak expression levels shortly after cells are stimulated withgrowth factors and sharply decrease thereafter. Several AU-richbinding proteins (AUBPs), including HuR (Hu-antigen R, Elavlikeprotein 1, ELAVL1) and KSRP (far upstream element-bindingprotein 2, KHSRP) bind to a fos AU-rich element (ARE) presentin the 3-UTR (untranslated region) of fos mRNA regulatingits stability by a still poorly defined mechanism. We showin the present study that, whereas HuR binds and stabilizestranscribed reporter mRNAs bearing the fos 3-UTR, KSRPcounteracts this effect. Furthermore, we found that fos mRNAstability and HuR phosphorylation status are dependent on theactivity of p38 MAPK in both epithelial cells and fibroblastsupon proliferative stimulation. Analysing PPI (protein?proteininteraction) networks, we performed a thorough query ofinteracting proteins for p38 MAPKs, HuR and other AUBPs upongrowth factor stimulation. This revealed novel HuR interactorsincluding inhibitors of protein phosphatase 2 (PP2A) activity.Over-expression of two of these interactors, pp32 and APRIL(acidic leucine-rich nuclear phosphoprotein 32 family member B,ANP32B) and pharmacological inhibition of PP2A stabilized a fosreporter mRNA. Our results indicate that p38 MAPK regulatesfos mRNA decay by affecting the state of phosphorylation ofHuR while controlling yet to be fully elucidated PP regulatorynetworks.