Activation of Mitogen-activated Protein Kinase by H2O2

In this study we investigated the factors controlling mitogen-activated protein kinase activation by H2O2 and explored the impact of altering the pathways to kinase activation on cell survival following H2O2 exposure

Kathryn Z. Guyton; Yusen Liu; Myriam Gorospe; Qingbo Xu; Nikki J. Holbrook

2002

Scholarcy highlights

  • The mitogen-activated protein kinase family is comprised of key regulatory proteins that control the cellular response to both proliferation and stress signals
  • To determine if ERK2 activation constitutes a widespread cellular response to oxidants such as H2O2, we examined the effect of H2O2on ERK2 in several cell types including HeLa, Rat1, NIH 3T3, and PC12 cell lines as well as in primary aortic smooth muscle cell cultures
  • Mannitol, a free radical scavenger with specificity for hydroxyl radical, blocked H2O2-mediated ERK2 activation. These results suggest that H2O2 undergoes metal-catalyzed conversion to a hydroxyl radical-like species and that oxidation by this free radical initiates signal transduction leading to ERK2 activation by H2O2
  • To determine if Ras is a component of the signaling cascade leading to ERK2 activation by H2O2, we examined the inhibitory effect of the dominant negative Ras-N-17 allele on ERK2 activation in PC12 cells(
  • We demonstrate that multiple members of the MAPK family are stimulated by H2O2 and that ERK2 in particular is highly activated in a variety of cell types
  • The involvement of newly synthesized proteins in regulating ERK2 activation following H2O2 exposure is precluded by both the rapidity of inactivation and the cycloheximide insensitivity of ERK2 activation
  • Expression of dominant negative Ras in PC12 cells and kinase-defective MEK in NIH 3T3 cells results in enhanced sensitivity to H2O2, while a constitutively active MEK variant engendered greater resistance

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