Tumor Cell Phenotype Is Sustained by Selective MAPK Oxidation in Mitochondria

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

Restoration of salt marshes in the Netherlands

The conquest of land from the sea has been a long tradition in the Netherlands. When salt marshes were high enough, they were embanked when it was economically feasible, and transformed into intensively exploited agricultural land. This resulted in the transformation of halophytic communities to glycophytic communities. Often as an alternative, a low levee, a summerdike was built, which greatly reduced the flooding frequency of the landward summerpolder, hence creating a sedimentation deficit therein. Such summerpolders now cover 1200 ha in the Netherlands, 2100 ha in NW-Germany and small areas in England. Due to continuous embankments, the present salt-marsh area is relatively small with respect to the tidal basins. Discussions have been started how to increase the salt-marsh area. Two options will be discussed, firstly de-embankment of summerpolders and maintenance of the protective seawall, secondly increase of the effects of saline seepage behind the seawall by top soil removal. Both options include the restoration of salt-marsh communities (target communities) in intensively agriculturally exploited sites that have been salt marshes before. From the few examples abroad and experiments it is discussed (1) to which extent the sedimentation deficit in summerpolders could be compensated for, (2) if the soil seed bank is likely to contribute to re-establishment of salt-marsh communities, (3) if the dispersal of propagules of halophytic plants will be possible by hydrochory when the summerdike is breached, (4) to what extent is dispersal by endozoochory through waterfowl important in case re-establishment in a saline seepage area behind the seawall without open connection to the sea is envisaged. Two case studies of de-embanked summerpolders in the Netherlands revealed that the sedimentation deficit can be counteracted by rapid sedimentation, provided enough transport is possible from the foreshore. Dispersal by incoming tidal water from the nearby salt-marsh source area into the target area is possible for many salt-marsh plant species. The rate of success seems to depend on the relative position of source area and target area. A case study in a saline seepage area after top soil removal in the Netherlands, showed that the number of viable seeds dispersed by droppings from waterfowl is limited. Hence the possibilities for restoration of inland halophytic plant communities seem much lower than after de-embankment of summerpolders