MEK1/2 overactivation can promote growth arrest by mediating ERK1/2-dependent phosphorylation of p70S6K
Jean-Philippe Guégan1, Frédéric Ezan, Luc Gailhouste
1UMR Inserm U1085 IRSET, Université de Rennes 1, UMS 3480 Biosit, Rennes, France.
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.
Insights
Overactivated extracellular signal-regulated kinase (ERK)1/2 signaling arrests the cell cycle by enhancing p21 translation via p70S6K. This pathway highlights translational control in cell cycle regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- The extracellular signal-regulated kinase (ERK)1/2 pathway regulates cell proliferation, with hyperactivation potentially causing cell cycle arrest.
- Kinase-independent functions of ERK1/2 in MAPK-induced growth arrest are not fully understood.
Purpose of the Study:
- To investigate the role of p70S6K in ERK1/2-mediated cell cycle arrest.
- To elucidate the mechanisms by which ERK1/2 overactivation leads to growth arrest.
Main Methods:
- Utilized MEK1/2 activation and ERK1/2 silencing (shRNA) in cell culture models.
- Assessed protein phosphorylation (p70S6K, S6) and expression (p21) using Western blotting.
- Employed kinase-dead ERK mutants to differentiate kinase-dependent and -independent effects.
- Investigated p21 mRNA translation, transcription, and protein stability.
Main Results:
- Overactivation of MEK1/2 by active mutants triggered G1 phase arrest, dependent on ERK1/2 activation of p70S6K.
- ERK1/2 silencing reduced p70S6K and S6 phosphorylation, and p21 expression, effects partially rescued by kinase-dead ERK mutants.
- p70S6K enhanced p21 mRNA translation but did not affect its transcription or stability.
Conclusions:
- The MEK1/2-ERK1/2-p70S6K pathway is crucial for cell cycle arrest induced by ERK1/2 hyperactivation.
- p70S6K mediates cell cycle arrest through translational upregulation of p21.
- This study highlights the significance of translational control in cell cycle regulation by the ERK pathway.
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