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PMID:10945608

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Citation

Yin, Z, Ivanov, VN, Habelhah, H, Tew, K and Ronai, Z (2000) Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res. 60:4053-7

Abstract

To elucidate mechanisms underlying glutathione S-transferase p (GSTp)-mediated cellular protection against oxidative stress-induced cell death, the effect of GSTp on stress signaling pathways was investigated before and after H2O2 treatment. Under nonstressed conditions, increased expression of GSTp via a tet-off-inducible GSTp in NIH 3T3 cells increased the phosphorylation of mitogen-activated protein (MAP) kinase kinase 4, p38, extracellular receptor kinase (ERK), and inhibitor of kappa-kinase (IKK), and reduced phosphorylation of MAP kinase kinase 7 and Jun NH2-terminal kinase (JNK). Whereas H2O2 treatment of cells induced JNK, p38, and IKK activities, in the presence of H2O2 and elevated GSTp expression there was an additional increase in ERK, p38, and IKK activities and a decrease in JNK activity. GSTp-mediated protection from H2O2-induced death was attenuated upon inhibition of p38, nuclear factor KB, or MAP kinase by dominant negative or pharmacological inhibitors. Conversely, expression of a dominant negative JNK protected cells from H2O2-mediated death. These data suggest that the coordinated regulation of stress kinases by GSTp, as reflected by increased p38, ERK, and nuclear factor kappaB activities together with suppression of JNK signaling, contributes to protection of cells against reactive oxygen species-mediated death.

Links

PubMed

Keywords

3T3 Cells; Animals; Cell Death/drug effects; Enzyme Activation; Glutathione Transferase/biosynthesis; Glutathione Transferase/physiology; Hydrogen Peroxide/metabolism; Hydrogen Peroxide/toxicity; I-kappa B Kinase; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; MAP Kinase Signaling System/drug effects; MAP Kinase Signaling System/physiology; Mice; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases/physiology; Mitogen-Activated Protein Kinases/metabolism; Mitogen-Activated Protein Kinases/physiology; NF-kappa B/antagonists & inhibitors; NF-kappa B/metabolism; NF-kappa B/physiology; Oxidative Stress/physiology; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Protein-Serine-Threonine Kinases/metabolism; Protein-Serine-Threonine Kinases/physiology; Reactive Oxygen Species/metabolism; p38 Mitogen-Activated Protein Kinases

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GSTP1

involved_in

GO:0000302: response to reactive oxygen species

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSTP1

involved_in

GO:0070372: regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSTP1

involved_in

GO:0032872: regulation of stress-activated MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSTP1

involved_in

GO:0043508: negative regulation of JUN kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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