Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults

Reactive oxygen species, generated by reduction-oxidation (redox) reactions, have been recognized as one of the major mediators of ischemia and reperfusion injury in the brain. Reactive oxygen species-induced cerebral events are attributable, in part, to the change in intracellular signaling molecul...

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Veröffentlicht in:The Journal of biological chemistry 2002-03, Vol.277 (11), p.9614-9621
Hauptverfasser: Suzaki, Yuki, Yoshizumi, Masanori, Kagami, Shoji, Koyama, A Hajime, Taketani, Yutaka, Houchi, Hitoshi, Tsuchiya, Koichiro, Takeda, Eiji, Tamaki, Toshiaki
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container_end_page 9621
container_issue 11
container_start_page 9614
container_title The Journal of biological chemistry
container_volume 277
creator Suzaki, Yuki
Yoshizumi, Masanori
Kagami, Shoji
Koyama, A Hajime
Taketani, Yutaka
Houchi, Hitoshi
Tsuchiya, Koichiro
Takeda, Eiji
Tamaki, Toshiaki
description Reactive oxygen species, generated by reduction-oxidation (redox) reactions, have been recognized as one of the major mediators of ischemia and reperfusion injury in the brain. Reactive oxygen species-induced cerebral events are attributable, in part, to the change in intracellular signaling molecules including mitogen-activated protein (MAP) kinases. Big MAP kinase 1 (BMK1), also known as ERK5, is a newly identified member of the MAP kinase family and has been reported to be sensitive to oxidative stress. In the present study, we examined the effect of H(2)O(2) on BMK1 activity in PC12 cells, and we investigated the pathophysiological implication of BMK1. Findings showed that BMK1 was rapidly and significantly activated by H(2)O(2) in a concentration-dependent manner in PC12 cells. BMK1 activation by H(2)O(2) was inhibited by both PD98059 and U0126, which were reported to inhibit MEK5 as well as MEK1/2. c-Src was suggested to be involved in BMK1 activation from the experiments with herbimycin A and PP2, specific inhibitors of Src family kinases. Transfection of kinase-inactive Src also inhibited H(2)O(2)-induced BMK1 activation. In addition, H(2)O(2) treatment of cells induced an enhancement of DNA binding activity of MEF2C, a downstream transcription factor of BMK1 in PC12 cells. Finally, pretreatment of cells with PD98059 and U0126 resulted in an increase in cell death including apoptosis by H(2)O(2) in ERK1/2 down-regulated cells as well as in intact PC12 cells. These findings suggest that c-Src mediated BMK1 activation by H(2)O(2) may counteract ischemic cellular damage probably through the activation of MEF2C transcription factor.
doi_str_mv 10.1074/jbc.M111790200
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These findings suggest that c-Src mediated BMK1 activation by H(2)O(2) may counteract ischemic cellular damage probably through the activation of MEF2C transcription factor.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>BMK1 protein</subject><subject>Butadienes - pharmacology</subject><subject>c-Src protein</subject><subject>Cell Survival</subject><subject>CSK Tyrosine-Protein Kinase</subject><subject>DNA - metabolism</subject><subject>Enzyme Activation - drug effects</subject><subject>ERK1/2 protein</subject><subject>ERK5 protein</subject><subject>Flavonoids - pharmacology</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>MEF2 Transcription Factors</subject><subject>MEF2C protein</subject><subject>Mitogen-Activated Protein Kinase 7</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Myogenic Regulatory Factors - metabolism</subject><subject>Nitriles - pharmacology</subject><subject>Oxidative Stress</subject><subject>PC12 Cells</subject><subject>PD98059</subject><subject>Protein-Tyrosine Kinases - physiology</subject><subject>Rats</subject><subject>Signal Transduction - drug effects</subject><subject>src-Family Kinases</subject><subject>U0126</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kMlOAzEMhnMAsV85Ip8QHAaytZNwg4pNUIEEnKtMkimBzMIk09L348HIsPhi2f78e0Fon-ATgnN--lbokykhJJeYYryGtjCmJJN0JDbRdghvOBmXZANtJkZQLsQW-rpZma6Z2xpa2zWfzlgI0VW9V9EG0NlTp7PKGpdCA4WbQ-XigGdKR7f4ybZdE62r4d3VKlggcHQxvSPHoGoD8dXC9PKKTiC4ea28q-fQqvi6VCtILY8TQkFb78MZtEmljk556Bpvh-pQgNB3izTIQ9l43ywHgWFNlaYPUOh9DLtovVQ-2L0_v4Neri6fJzfZ_cP17eT8PmspEzGTpSyYlrq0Y46VKIzhBadUGiYUY7gYkbyQnEtDOWbK5HbMtBBWKzHW5Sg3bAcd_uqmkz96G-KscmHYUtW26cOMCCoxzmUCD_7Avkjfm7Wdq1S3mv3_nX0DEueGew</recordid><startdate>20020315</startdate><enddate>20020315</enddate><creator>Suzaki, Yuki</creator><creator>Yoshizumi, Masanori</creator><creator>Kagami, Shoji</creator><creator>Koyama, A Hajime</creator><creator>Taketani, Yutaka</creator><creator>Houchi, Hitoshi</creator><creator>Tsuchiya, Koichiro</creator><creator>Takeda, Eiji</creator><creator>Tamaki, Toshiaki</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TM</scope></search><sort><creationdate>20020315</creationdate><title>Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults</title><author>Suzaki, Yuki ; 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subjects Animals
Apoptosis
BMK1 protein
Butadienes - pharmacology
c-Src protein
Cell Survival
CSK Tyrosine-Protein Kinase
DNA - metabolism
Enzyme Activation - drug effects
ERK1/2 protein
ERK5 protein
Flavonoids - pharmacology
Hydrogen Peroxide - pharmacology
MEF2 Transcription Factors
MEF2C protein
Mitogen-Activated Protein Kinase 7
Mitogen-Activated Protein Kinases - metabolism
Myogenic Regulatory Factors - metabolism
Nitriles - pharmacology
Oxidative Stress
PC12 Cells
PD98059
Protein-Tyrosine Kinases - physiology
Rats
Signal Transduction - drug effects
src-Family Kinases
U0126
title Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults
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