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

• Published in: The FEBS journal 2015-02, Vol.282 (4), p.613-629
• Main Authors: Nagashima, Takeshi, Inoue, Norihiko, Yumoto, Noriko, Saeki, Yuko, Magi, Shigeyuki, Volinsky, Natalia, Sorkin, Alexander, Kholodenko, Boris N., Okada‐Hatakeyama, Mariko
• Format: Article
• Language: English
• Subjects: Butadienes - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - physiology; Dactinomycin - pharmacology; Editor's Choice; EGFR; ERK; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Genes; Humans; Kinases; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; MCF-7 Cells; mRNA stability; Nitriles - pharmacology; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; RNA Stability - drug effects; RNA Stability - genetics; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; transcriptome
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13172

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. Extracellular signal‐regulated kinase, ERK, plays a critical role in regulating cell growth and differentiation, depending on its signal duration. Although much is known about the effects of ERK signaling on downstream target proteins, little is known about how ERK might affect mRNA stability. In this paper, Nagashima and colleagues show that prolonged ERK activation can directly contribute to the stabilisation of late‐response mRNAs, and propose that this feed‐forward regulation of mRNA stability plays an important role in cell fate decisions.