Activation of Mitogen-activated Protein Kinase by HO ROLE IN CELL SURVIVAL FOLLOWING OXIDANT INJURY

来自 Semantic Scholar

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阅读量：

111

作者：

KZ Guyton，Y Liu，M Gorospe，Q Xu，NJ Holbrook

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摘要：

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 HOand explored the impact of altering the pathways to kinase activation on cell survival following HOexposure. Potent activation (10-20-fold) of extracellular signal-regulated protein kinase (ERK2) occurred within 10 min of HOtreatment, whereupon rapid inactivation ensued. HOactivated ERK2 in several cell types and also moderately activated (3-5-fold) both c-Jun N-terminal kinase and p38/RK/CSBP. Additionally, HOincreased the mRNA expression of MAPK-dependent genes c-, c-, and MAPK phosphatase-1. Suramin pretreatment completely inhibited HOstimulation of ERK2, highlighting a role for growth factor receptors in this activation. Further, ERK2 activation by HOwas blocked by pretreatment with either -acetyl-cysteine, -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 HOtoxicity. Moreover, NIH 3T3 cells expressing constitutively active MAPK kinase (MEK, the immediate upstream regulator of ERK) were more resistant to HOtoxicity, 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 HOand suggest that ERK plays a critical role in cell survival following oxidant injury.

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关键词：

habitat models trout biomass streams New Mexico management

DOI：

doi:10.1074/jbc.271.7.3604

被引量：

2210

年份：

1996