Parallel and independent regulation of interleukin-3 mRNA turnover by phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase

AU-rich elements (ARE) present in the 3' untranslated regions of many cytok ines and immediate-early genes are responsible for targeting the transcript s for rapid decay. We present evidence from cotransfection experiments in N IH 3T3 cells that two signaling pathways, one involving phosphatidylinosito l 3-kinase (PI3-K), and one involving the p38 mitogen-activated protein kin ase (MAPK), lead to stabilization of interleukin-3 mRNA in parallel. Stabil ization mediated by either of the two pathways was antagonized by tristetra prolin (ITP), an AU-binding protein known to promote constitutive decay of ARE-containing transcripts. Remarkably, the stabilizing AU-binding protein HuR, in collaboration with p38 MAPK but not with PI3-K, could overcome the destabilizing effect of TTP. These data argue that the stabilizing kinases PI3-K and p38 MAPK do not act through direct inactivation of TTP but via ac tivating pathway-specific stabilizing AU-binding proteins. Our data suggest an integrated model of mRNA turnover control, where stabilizing (HuR) and destabilizing (TTP) AU-binding proteins compete and where the former are un der the positive control of independent phosphokinase signaling pathways.