The p42/p44 Mitogen-activated Protein Kinase Activation Triggers p27Kip1 Degradation Independently of CDK2/Cyclin E in NIH 3T3 Cells

Delmas, Christelle; Manenti, Stéphane; Boudjelal, Aicha; Peyssonnaux, Carole; Eychène, Alain; Darbon, Jean‐Marie

doi:10.1074/jbc.m101714200

Cited by 59 publications

(51 citation statements)

References 58 publications

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“…In fibroblasts, activa-tion of MAP kinases leads to an increase in p27 Kip1 degradation that is independent of phosphorylation by CDK2/cyclin E [39,40,41]. In contrast, a more delayed and prolonged activation of MAP kinases, for example induced in PC12 cells and fibroblasts by nerve growth factor, leads to cell cycle arrest [42].…”

Section: Discussionmentioning

confidence: 99%

Erk 1,2 phosphorylates p27 Kip1 : Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

et al. 2003

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Aims/hypothesis. Mesangial cell hypertrophy is one of the earliest morphological abnormalities of diabetic nephropathy. We have previously shown that high glucose induces p27 Kip1 by a post-transcriptional mechanism and that mesangial cell hypertrophy depends on G 1 -phase arrest mediated by this CDK-inhibitor. However, it remains poorly understood how high glucose stimulates p27 Kip1 expression in mesangial cells. Methods. Mesangial cells were isolated from p27 Kip1 +/+ and -/-mice and characterized by light microscopy and immunohistochemistry. It was tested by Western blotting and autoradiography whether high glucose medium activates Erk 1,2 and whether this activation phosphorylates p27 Kip1 . The three consensus phosphorylation sites of p27 Kip1 were mutated and these constructs were expressed in p27 Kip1 -/-mesangial cells. Hypertrophy was assessed by different methods.Results. High glucose stimulates phosphorylation of MAP kinases Erk 1,2 in p27 Kip1 +/+ and -/-mesangial cells. Activation of Erk 1,2 leads to phosphorylation of p27 Kip1 in vitro and in vivo . Mutations of serine 10 or threonine 187 still supported high glucose-induced hypertrophy. In contrast, a mutation of serine 178 converted the hypertrophic response into a proliferative phenotype. Mutation of serine 178 leads to the attenuated expression of p27 Kip1 protein in the presence of high glucose. Conclusions/interpretation. Our study shows that high glucose stimulates Erk 1,2 that phosphorylate p27 Kip1 at serine 178 increasing its expression. This is an important molecular mechanism of high glucose-induced hypertrophy of mesangial cells. [Diabetologia (2003[Diabetologia ( ) 46:1090[Diabetologia ( -1099

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Section: Discussionmentioning

confidence: 99%

Erk 1,2 phosphorylates p27 Kip1 : Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

et al. 2003

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“…Inhibition of ERK by PD98059 causes an accumulation of p27 as well as the S phase entry in fibroblasts and epithelial cells (33), suggesting that the ERK cascade is required for both mitogen-induced p27 down-regulation and proliferation. Furthermore, genetic activation of ERK decreased the expression of p27 in NIH 3T3 cells (34).…”

Section: Figmentioning

confidence: 95%

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Sakakibara

Kubota

Worku

et al. 2005

Journal of Biological Chemistry

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Cyclin-dependent kinase inhibitor p27, a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals during arterial injury. In this study, we show in rat aortic smooth muscle cells that PDGF-BB down-regulated p27 protein and mRNA in an ERK-dependent mechanism. Inhibition of ERK, but not other subtypes of the mitogen-activated protein kinase family, prevented the reduction of p27 protein and mRNA. Conversely, direct activation of ERK via adenovirus-mediated expression of a constitutively active form of MEK led to a reduction of p27 protein and mRNA, further supporting the central role of ERK in regulation of p27 expression. Rapamycin, which potently inhibited PDGF-induced activation of p70 S6 kinase as well as proliferation of smooth muscle cells, did not alter the expression of p27. To delineate the molecular mechanism underlying the p27 down-regulation, we examined the effect of PDGF-BB on p27 promoter activity as well as mRNA stability. Stimulation with PDGF-BB significantly shortened the half-life of p27 mRNA without affecting its promoter activity. To further understand the PDGF-stimulated p27 mRNA turnover, we inserted the 5-and/or 3-untranslated regions of p27 cDNA into a non-PDGF-responsive luciferase gene. Only those chimeric genes that contained the 3-untranslated region responded to PDGF-BB with reduced expression. Moreover, inhibition of ERK completely prevented the effect of PDGF on the chimera expression. In summary, our data suggest that p27 is down-regulated by PDGF-BB in vascular smooth muscle cells through an ERK-dependent posttranscriptional mechanism.

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“…The levels of p27 are high in quiescent cells and decline in response to mitogenic factor stimulation. Several studies have suggested that the Ras-ERK1/2 signaling pathway is involved in the mitogen-induced downregulation of p27 (Kawada et al, 1997;Kerkhoff and Rapp, 1997;Woods et al, 1997;Greulich and Erikson, 1998;Rivard et al, 1999;Treinies et al, 1999;Lenferink et al, 2000;Yang et al, 2000;Delmas et al, 2001;Mirza et al, 2004;Gysin et al, 2005;Sakakibara et al, 2005). In contrast, other studies failed to document any significant change in p27 levels following inhibition of ERK1/2 signaling by synthetic MEK1/2 inhibitors or dominant-negative ERK2, or after conditional activation of the pathway by activated Raf-1 or MEK1 (Sewing et al, 1997;Takuwa and Takuwa, 1997;Weber et al, 1997a;Cheng et al, 1998;Ladha et al, 1998;Chen et al, 1999;Tetsu and McCormick, 2003).…”

Section: Erk1/2 Map Kinases In Cell Cycle Control S Meloche and J Poumentioning

confidence: 99%

“…The degradation of p27 at the G1/S transition depends on the accumulation of cyclin E and concomitant activation of Cdk2, events that are conditional on earlier activation of cyclin D-Cdk4/6 complexes by the ERK1/2 pathway. However, there is evidence that ERK1/2 signaling can trigger downregulation of p27 expression by a Cdk2-and Skp2-independent mechanism (Delmas et al, 2001;Mirza et al, 2004). Activation of the ERK1/2 pathway may also contribute indirectly to p27 regulation through the synthesis of autocrine growth factors.…”

Section: Erk1/2 Map Kinases In Cell Cycle Control S Meloche and J Poumentioning

confidence: 99%

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

2007

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The Ras-dependent extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway plays a central role in cell proliferation control. In normal cells, sustained activation of ERK1/ERK2 is necessary for G1-to S-phase progression and is associated with induction of positive regulators of the cell cycle and inactivation of antiproliferative genes. In cells expressing activated Ras or Raf mutants, hyperactivation of the ERK1/2 pathway elicits cell cycle arrest by inducing the accumulation of cyclin-dependent kinase inhibitors. In this review, we discuss the mechanisms by which activated ERK1/ERK2 regulate growth and cell cycle progression of mammalian somatic cells. We also highlight the findings obtained from gene disruption studies.

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The p42/p44 Mitogen-activated Protein Kinase Activation Triggers p27Kip1 Degradation Independently of CDK2/Cyclin E in NIH 3T3 Cells

Cited by 59 publications

References 58 publications

Erk 1,2 phosphorylates p27 Kip1 : Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

Erk 1,2 phosphorylates p27 Kip1 : Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

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