Tumor Cell Phenotype Is Sustained by Selective MAPK Oxidation in Mitochondria
Open Access
- 11 June 2008
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 3 (6), e2379
- https://doi.org/10.1371/journal.pone.0002379
Abstract
Mitochondria are major cellular sources of hydrogen peroxide (H2O2), the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H2O2 concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H2O2 due to defective mitochondrial metabolism can contribute to sustain proliferation. Mitogen-activated protein kinases (MAPKs) orchestrate signal transduction and recent data indicate that are present in mitochondria and regulated by the redox state. On these bases, we investigated the mechanistic connection of tumor mitochondrial dysfunction, H2O2 yield, and activation of MAPKs in LP07 murine tumor cells with confocal microscopy, in vivo imaging and directed mutagenesis. Two redox conditions were examined: low 1 µM H2O2 increased cell proliferation in ERK1/2-dependent manner whereas high 50 µM H2O2 arrested cell cycle by p38 and JNK1/2 activation. Regarding the experimental conditions as a three-compartment model (mitochondria, cytosol, and nuclei), the different responses depended on MAPKs preferential traffic to mitochondria, where a selective activation of either ERK1/2 or p38-JNK1/2 by co-localized upstream kinases (MAPKKs) facilitated their further passage to nuclei. As assessed by mass spectra, MAPKs activation and efficient binding to cognate MAPKKs resulted from oxidation of conserved ERK1/2 or p38-JNK1/2 cysteine domains to sulfinic and sulfonic acids at a definite H2O2 level. Like this, high H2O2 or directed mutation of redox-sensitive ERK2 Cys214 impeded binding to MEK1/2, caused ERK2 retention in mitochondria and restricted shuttle to nuclei. It is surmised that selective cysteine oxidations adjust the electrostatic forces that participate in a particular MAPK-MAPKK interaction. Considering that tumor mitochondria are dysfunctional, their inability to increase H2O2 yield should disrupt synchronized MAPK oxidations and the regulation of cell cycle leading cells to remain in a proliferating phenotype.Keywords
This publication has 55 references indexed in Scilit:
- A Mitochondrial Kinase Complex Is Essential to Mediate an ERK1/2-Dependent Phosphorylation of a Key Regulatory Protein in Steroid BiosynthesisPLOS ONE, 2008
- Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanismThe Journal of cell biology, 2006
- Differential expression of STAT5 and Bcl-xL, and high expression of Neu and STAT3 in non-small-cell lung carcinomaLung Cancer, 2006
- Docking Interactions Induce Exposure of Activation Loop in the MAP Kinase ERK2Structure, 2006
- Redox Regulation of MAP Kinase Phosphatase 3Biochemistry, 2006
- Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125The EMBO Journal, 2004
- Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3‐kinase activationJournal of Neurochemistry, 2003
- Activation of JNK by Epac Is Independent of Its Activity as a Rap Guanine Nucleotide ExchangerJournal of Biological Chemistry, 2003
- The Modulation of Mitochondrial Nitric-oxide Synthase Activity in Rat Brain DevelopmentPublished by Elsevier BV ,2002
- The Broad Spectrum of Responses to Oxidants in Proliferating Cells: A New Paradigm for Oxidative StressIUBMB Life, 1999