Mitogen-activated protein kinase kinase 7 is activated during low potassium-induced apoptosis in rat cerebellar granule neurons.
A stress-activated protein kinase pathway comprising mitogen-activated protein kinase kinases (MKKs), c-Jun N-terminal kinase (JNK) and the transcription factor c-Jun is implicated in neuronal apoptosis. Using an immune-complex kinase assay, we measured the activation of MKK4 and MKK7 in low potassium (LK)-induced apoptosis of rat cerebellar granule neurons (CGN). MKK7, but not MKK4, was activated within the first 4-6 h in four independent sets of 14-h CGN apoptosis time-courses. CEP-1347 (500 nM), an mixed-lineage kinase 3 inhibitor, prevented MKK7 activation and cell death following exposure of CGN cultures to LK-induced apoptosis. Western blot analysis revealed that levels of phosphorylated c-Jun were elevated between 30 min and 10 h of CGN apoptosis, temporally consistent with MKK7 activation. These data suggest that MKK7 is responsible for activating the JNK pathway during LK-induced CGN apoptosis.
Trotter
Linda
L
Discovery Biology, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK.
Panton
Wendy
W
Hajimohamadreza
Iradj
I
Petalidis
Lawrence
L
Ward
Robin
R
Fleming
Yvonne
Y
Armstrong
Christopher G
CG
Cohen
Philip
P
Karran
Eric H
EH
Kinloch
Ross A
RA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000187:drug effects / Q000201:enzymology; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011191:Potassium Deficiency / Q000201:enzymology* / Q000503:physiopathology; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases