The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition ERK1/2 MAP kinases in cell cycle control

Departments of Pharmacology and Molecular Biology, Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, Quebec, Canada.
Oncogene (Impact Factor: 8.46). 06/2007; 26(22):3227-39. DOI: 10.1038/sj.onc.1210414
Source: PubMed


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.

Download full-text


Available from: Jacques Pouysségur, Mar 26, 2015
28 Reads
  • Source
    • "In diverse cell types, including fibroblasts, ERK1/2 activation in response to mitogenic stimuli promotes cell proliferation [53]. In particular, a number of evidence indicates that sustained activation of ERK1/2 signaling is required for G1-to S-phase progression and is accompanied by induction of positive regulators of cell cycle [54]. Furthermore, LPA has long been known to stimulate fibroblasts proliferation through PTX-sensitive G proteins [35] [36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Different lines of evidence indicate that the lysophosphatidic acid (LPA) receptor LPA1 is involved in neurogenesis, synaptic plasticity and anxiety-related behaviour, but little is known on whether this receptor can be targeted by neuropsychopharmacological agents. The present study investigated the effects of different antidepressants on LPA1 signaling. We found that in Chinese hamster ovary (CHO)-K1 fibroblasts expressing endogenous LPA1 tricyclic and tetracyclic antidepressants and fluoxetine induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and CREB. This response was antagonized by either LPA1 blockade with Ki16425 and AM966 or knocking down LPA1 with siRNA. Antidepressants induced ERK1/2 phosphorylation in human embryonic kidney (HEK)-293 cells overexpressing LPA1, but not in wild type cells. In PathHunter™ assay measuring receptor-β-arrestin interaction, amitriptyline, mianserin and fluoxetine failed to induce activation of LPA2 and LPA3. stably expressed in CHO-K1 cells. ERK1/2 stimulation by antidepressants and LPA was suppressed by pertussis toxin and inhibition of Src, phosphatidylinositol-3 kinase and insulin-like growth factor-I receptor (IGF-IR) activities. Antidepressants and LPA induced tyrosine phosphorylation of IGF-IR and insulin receptor-substrate-1 through LPA1 and Src. Prolonged exposure of CHO-K1 fibroblasts to either mianserin, mirtazapine or LPA enhanced cell proliferation as indicated by increased [(3)H]-thymidine incorporation and Ki-67 immunofluorescence. This effect was inhibited by blockade of LPA1- and ERK1/2 activity. These data provide evidence that different antidepressants induce LPA1 activation, leading to receptor tyrosine kinase transactivation, stimulation of ERK1/2 signaling and enhanced cell proliferation. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 04/2015; 95(4). DOI:10.1016/j.bcp.2015.04.002 · 5.01 Impact Factor
  • Source
    • "These findings indicate that the diabetes-induced RPE cell proliferation may be mediated by ERK signaling. The ERK1 (p44) and ERK2 (p22) are known to be activated by mitogenic factors and that this biochemical change stimulates cell division (Meloche and Pouyssegur, 2007). As the cell proliferation was investigated at the early stage, that is, at the end of second week, the low or moderate level of oxidative stress might have stimulated the expression of the ERKs to mediate the cell proliferation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although diabetes induces retinopathy its effects on retinal pigment epithelium (RPE) are not clearly known. The present study investigated the effects of streptozotocin-induced diabetes on RPE cell proliferation and the expression of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinases (JNKs) in rats. The bromodeoxyuridine immunohistochemistry revealed diabetes induced RPE cell proliferation at the end of first and second weeks in dark Agouti rats and at the end of first week in Wistar rats, but it inhibited the proliferation in both strains at the end of fifth week (P < 0.05). A further analysis at the end of second week in the dark Agouti rats showed the cell proliferation, but not apoptosis, in association with an increase in ERK1/2 expression (P < 0.05). However, the increased ERK level did not affect the expression of one of its substrates, the transcription factor c-Fos, suggesting that this protein has no role in the induction of the RPE cell proliferation. On the other hand, although total JNKs showed a decrease in the diabetic group (P < 0.05), the JNKp46 isoform was increased and the JNKp54 isoform was decreased, but without any effects on one of their substrates, the transcription factor, c-Myc. Our results indicate that the RPE cell proliferation in diabetic rats may be mediated through mitogen-activated protein kinases. Thus, modulation of mitogen-activated protein kinases signaling may be a putative therapeutic option to alleviate the genesis of diabetes-induced retinal disruptions including retinopathy.
    Experimental and Toxicologic Pathology 11/2014; 67(2). DOI:10.1016/j.etp.2014.10.006 · 1.86 Impact Factor
  • Source
    • "There is now much evidence to suggest that the proliferation of many cell types is under the control of redoxregulated signalling pathways (reviewed in [5]). In particular the ERK1/2 signalling cascade, activated by intracellular-generated reactive oxygen species (ROS) acts to promote proliferation in various cell types [6] [7] [8]. An important molecular mechanism underlying this ERK1/2 activation is thought to be the ROS-dependent inactivation of protein tyrosine phosphatases (PTPs) (reviewed in [9]). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiomyocyte cell cycling is under redox control in vivo•Nox4 is a potential source of ROS regulating this process•Redox activation of ERK1/2 promotes cyclin D2 transcription via c-myc activation•Promotion of proliferation via increased cyclin D2 may be useful therapeutically
    Journal of Molecular and Cellular Cardiology 11/2014; 79. DOI:10.1016/j.yjmcc.2014.10.017 · 4.66 Impact Factor
Show more