title: MEK1/2 overactivation can promote growth arrest by mediating ERK1/2-dependent phosphorylation of p70S6K.
abstract: The extracellular signal-regulated kinase (ERK)1/2 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.
authors: UMR Inserm U1085 IRSET, Université de Rennes 1, UMS 3480 Biosit, Rennes, France.
authors: Jean-Philippe
authors: JP
authors: Guégan
authors: Frédéric
authors: F
authors: Ezan
authors: Luc
authors: L
authors: Gailhouste
authors: Sophie
authors: S
authors: Langouët
authors: Georges
authors: G
authors: Baffet
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000096:biosynthesis / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; C482128:MAP2K2 protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human