MEK1-2 Overactivation Can Promote Growth Arrest by Mediating ERK1-2-Dependent Phosphorylation of p70S6KReport as inadecuate

MEK1-2 Overactivation Can Promote Growth Arrest by Mediating ERK1-2-Dependent Phosphorylation of p70S6K - Download this document for free, or read online. Document in PDF available to download.

* Corresponding author 1 Irset - Institut de recherche, santé, environnement et travail Rennes 2 Division of Molecular and Cellular Medicine

Abstract : The extracellular signal-regulated kinase ERK1-2 mitogen-activated protein MAP kinase pathway has been involved in the positive and negative regulation of cell proliferation. Upon mitogen stimulation, ERK1-ERK2 activation is necessary for G1- to S-phase progression whereas when hyperactived, this pathway could elicit cell cycle arrest. The mechanisms involved are not fully elucidated but a kinase-independent function of ERK1-2 has been evidenced in the MAPK-induced growth arrest. Here, we show that p70S6K, a central regulator of protein biosynthesis, is essential for the cell cycle arrest induced by overactivation of ERK1-2. Indeed, whereas MEK1 silencing inhibits cell cycle progression, we demonstrate that active mutant form of MEK1 or MEK2 triggers a G1 phase arrest by stimulating an activation of p70S6K by ERK1-2 kinases. Silencing of ERK1-2 activity by shRNA efficiently suppresses p70S6K phosphorylation on Thr421-Ser424 and S6 phosphorylation on Ser240-244 as well as p21 expression, but these effects can be partially reversed by the expression of kinase-dead mutant form of ERK1 or ERK2. In addition, we demonstrate that the kinase p70S6K modulates neither the p21 gene transcription nor the stability of the protein but enhances the translation of the p21 mRNA. In conclusion, our data emphasizes the importance of the translational regulation of p21 by the MEK1-2-ERK1-2-p70S6K pathway to negatively control the cell cycle progression. J. Cell. Physiol. 229: 903-915, 2014. © 2013 Wiley Periodicals, Inc.

keyword : MAPK ERK hepatocellular carcinoma proliferation cell cycle

Author: Jean-Philippe Guégan - Frédéric Ezan - Luc Gailhouste - Sophie Langouët - Georges Baffet -



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