RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Suzaki, Y  Yoshizumi, M  Kagami, S  Koyama, AH  Taketani, Y  Houchi, H  Tsuchiya, K  Takeda, E  Tamaki, T 
Citation: Suzaki Y, etal., J Biol Chem. 2002 Mar 15;277(11):9614-21. Epub 2002 Jan 8.
RGD ID: 2298794
Pubmed: PMID:11782488   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M111790200   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ERK5 cascade  IMP 2298794 RGD 
MAPK cascade  IMP 2298794 RGD 
protein autophosphorylation  IDA 2298794 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ATP binding  IDA 2298794 RGD 
DNA binding  IDA 2298794 RGD 
MAP kinase activity  IDA 2298794 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Erk5 MAPK signaling pathway   ISOMapk7 (Rattus norvegicus)2298794; 2298794 RGD 
Erk5 MAPK signaling pathway   IMP 2298794 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Mapk7  (mitogen-activated protein kinase 7)
Mef2c  (myocyte enhancer factor 2C)

Genes (Mus musculus)
Mapk7  (mitogen-activated protein kinase 7)

Genes (Homo sapiens)
MAPK7  (mitogen-activated protein kinase 7)


Additional Information