Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria.
Mitochondria are major cellular sources of hydrogen peroxide (H(2)O(2)), the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H(2)O(2) concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H(2)O(2) 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, H(2)O(2) 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 microM H(2)O(2) increased cell proliferation in ERK1/2-dependent manner whereas high 50 microM H(2)O(2) 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 H(2)O(2) level. Like this, high H(2)O(2) or directed mutation of redox-sensitive ERK2 Cys(214) 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 H(2)O(2) yield should disrupt synchronized MAPK oxidations and the regulation of cell cycle leading cells to remain in a proliferating phenotype.
Galli
Soledad
S
Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, Buenos Aires, Argentina.
Antico Arciuch
Valeria Gabriela
VG
Poderoso
Cecilia
C
Converso
Daniela Paola
DP
Zhou
Qiongqiong
Q
Bal de Kier Joffé
Elisa
E
Cadenas
Enrique
E
Boczkowski
Jorge
J
Carreras
María Cecilia
MC
Poderoso
Juan José
JJ
D000818:Animals; D002384:Catalysis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D010084:Oxidation-Reduction; D010641:Phenotype; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction
D020928:Mitogen-Activated Protein Kinases