Feedforward regulation of mRNA stability by prolonged extracellular signal-regulated kinase activity

Extracellular signal-regulated kinase (ERK) plays a central role in signal transduction networks and cell fate decisions. Sustained ERK activation induces cell differentiation, whereas transient ERK results in the proliferation of several types of cells. Sustained ERK activity stabilizes the proteins of early-response gene products. However, the effect of ERK activity duration on mRNA stability is unknown. We analyzed the quantitative relationship between the duration of four ERK activity kinetics and the mRNA expression profile in growth factor-treated cells. Time-course transcriptome analysis revealed that the cells with prolonged ERK activity generally showed sustained mRNA expression of late response genes but not early or mid genes. Selected late response genes decayed more rapidly in the presence of a specific ERK inhibitor than a general transcription inhibitor and the decay rate was not related to the number of AU-rich elements. Our results suggest that sustained ERK activity plays an important role in the lifespan of the mRNA encoded by late response genes, in addition to the previously demonstrated role in protein stabilization of early-response genes, including transcription factors regulating the transcription of mid and late genes. This double-positive regulation of ligand-induced genes, also termed feedforward regulation, is critical in cell fate decisions.