Investigating the neuroprotective mechanism of action of a CDK5 inhibitor by phosphoproteome analysis.
J Cell Biochem
; 95(4): 817-26, 2005 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-15838870
ABSTRACT
Small molecule inhibitors of cyclin-dependent kinase 5 (CDK5) protect neurons from cell death following various insults. To elucidate the cellular mechanism of action we investigated changes in protein phosphorylation in cultured rat cerebellar granule neurons after administration of the CDK5 inhibitor Indolinone A. By immunoblot analysis we detected enhanced phosphorylation of the extracellular signal-regulated kinase1/2 (ERK1/2) and the Jun N-terminal kinase (JNK) substrate c-Jun. Co-administration of U0126, an inhibitor of ERK1/2, or SP600125, an inhibitor of JNK, blocked phosphorylation of ERK1/2 or c-Jun, but did not affect neuroprotection by the CDK5 inhibitor. By metal affinity chromatography, two-dimensional (2D) gel electrophoresis, and MALDI-TOF mass spectrometry we identified several phosphoproteins that accumulated in neurons treated with Indolinone A. Among them were proteins involved in neurotransmitter release, which is consistent with a physiological function of CDK5 in synaptic signaling. Moreover, we identified proteins acting in energy metabolism, protein folding, and oxidative stress response. Similar findings have been reported in yeast following inhibition of Pho85 kinase, which is homologous to mammalian CDK5 and acts in environmental stress signaling. These results suggest that inhibition of CDK5 activates stress responsive proteins that may protect neurons against subsequent injurious stimuli.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
/
Fármacos Neuroprotetores
/
Quinases Ciclina-Dependentes
/
Proteoma
/
Proteômica
/
Inibidores de Proteínas Quinases
/
Indóis
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Cell Biochem
Ano de publicação:
2005
Tipo de documento:
Article