Activation of Mitogen-activated Protein Kinase by HO

The mitogen-activated protein kinase (MAPK) family is comprised of key regulatory proteins that control the cellular response to both proliferation and stress signals. In this study we investigated the factors controlling MAPK activation by HO and explored the impact of altering the pathways to kinase activation on cell survival following HO exposure. Potent activation (10-20-fold) of extracellular signal-regulated protein kinase (ERK2) occurred within 10 min of HO treatment, whereupon rapid inactivation ensued. HO activated ERK2 in several cell types and also moderately activated (3-5-fold) both c-Jun N-terminal kinase and p38/RK/CSBP. Additionally, HO increased the mRNA expression of MAPK-dependent genes c-jun, c-fos, and MAPK phosphatase-1. Suramin pretreatment completely inhibited HO stimulation of ERK2, highlighting a role for growth factor receptors in this activation. Further, ERK2 activation by HO was blocked by pretreatment with either N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating that metal-catalyzed free radical formation mediates the initiation of signal transduction by HO. HO-stimulated activation of ERK2 was abolished in PC12 cells by inducible or constitutive expression of the dominant negative Ras-N-17 allele. Interestingly, PC12/Ras-N-17 cells were more sensitive than wild-type PC12 cells to HO toxicity. Moreover, NIH 3T3 cells expressing constitutively active MAPK kinase (MEK, the immediate upstream regulator of ERK) were more resistant to HO toxicity, while those expressing kinase-defective MEK were more sensitive, than cells expressing wild-type MEK. Taken together, these studies provide insight into mechanisms of MAPK regulation by HO and suggest that ERK plays a critical role in cell survival following oxidant injury.

• Publication year

  1996

• Venue

  Journal of Biological Chemistry

• Publication date

  1996-02-23

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.271.8.4138PMID 8626753
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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