INVESTIGADORES
PODEROSO Juan Jose
congresos y reuniones científicas
Título:
l peróxido de hidrógeno modula la progresión del ciclo celular en células tumorales.
Autor/es:
GALLI S; LABATO M; CARRERAS MC; PODEROSO JJ
Lugar:
La Plata, Buenos Aires
Reunión:
Jornada; XI Jornadas de Jóvenes Investigadores de AUGM.; 2003
Resumen:
Mammalian cells express múltiple mitogen- activated protein kinases (MAPK) that mediate the effects of extracellular signals on a wide array of biological processes. In eukaryotic cells, three distinct MAPK cascades have been described, which appear to be linked to separate signal transduction pathways, resulting in the activation of either P42/44 (ERK1/2), p38 MAPK or stress activated protein kinases (SAPK/JNK). Depending on the cellular context, extracellular signals can elicit a specific cellular response such as proliferation, cell cycle arrest or apoptosis, through the preferential activation of one of the MAPK cascades. Reactive oxygen species (ROS) are generated during oxidative cell metabolism, and particularly in mitochondria. Recent studies involve ROS in the normal physiological signalling elicited by growth factors and cytokines. It is accepted that hydrogen peroxide promotes (H2O2) tyrosine phosphorylation in proteins, including ERK1/2 and p38. The relation between mitochondrial H2O2 production and its degradation by cytosolic catalase and glutathion peroxidase generate an intracellular H2O2 steady state ([H2O2]ss). Proliferating tissues (fetal and neonate rat brain and liver), and tumors show a low  [H2O2]ss, while quiescent tissues (adult liver) display a 2-fold higher [H2O2]ss. On these basis, the aim of this work is to study hydrogen peroxide modulation of cell cycle progression, discerning the effect on MAPKs and relating the effects to the proliferative state of a tumoral cell line, LP07. Results: by proliferation assays we demonstrated that 1 uM H2O2 elicit LP07 proliferation, while higher doses (>10 uM) generate cell cycle arrest and apoptosis. In addition, H2O2 promotes the phosphorylation and activation of ERK1/2, p38 MAPK and SAPK/JNK. 1 uM H2O2 elicit a persistent and slow kinetic ERK1/2 activation. On the other hand, 50 uM H2O2 drives a fast phosphorylation followed by a rapid decay. 1 uM H2O2 also promotes the synthesis of cyclin D1, while 50 uM exerts an inhibitory effect. Treatment of the cells with a MEK1/2 inhibitor (U0126), an upstream ERK1/2 kinase, we observed a block in the induction of cyclin D1 when stimulated with 1 uM H2O2. This suggests that the proliferative signal elicited by H2O2 is through ERK1/2. We also observed an augment of ERK1/2 activity in LP07 mitochondria, which suggests that the phosphorylation of ERK1/2 could occur in this organelle. In conclusion, these data suggest that persistent tumoral proliferation can be due to the differential activity of MAPK, elicited by the intracellular H2O2 concentration in transformed cells.