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Cisplatin‐mediated activation of extracellular signal‐regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases
Author(s) -
Gozdz Agata,
Vashishta Aruna,
Kalita Katarzyna,
Szatmari Erzsebet,
Zheng JingJuan,
Tamiya Shigeo,
Delamere Nicholas A.,
Hetman Michal
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05550.x
Subject(s) - dephosphorylation , kinase , phosphatase , phosphorylation , neurodegeneration , dusp6 , cisplatin , biology , microbiology and biotechnology , activator (genetics) , dual specificity phosphatase , chemistry , biochemistry , receptor , medicine , protein phosphatase 2 , disease , genetics , chemotherapy
The mechanism(s) underlying neurodegeneration‐associated activation of ERK1/2 remain poorly understood. We report that in cultured rat cortical neurons, whose basal ERK1/2 phosphorylation required NMDA receptors (NMDAR), the neurotoxic DNA intercalating drug cisplatin increased ERK1/2 phosphorylation via NMDAR despite reducing their activity. The rate of ERK1/2 dephosphorylation was lowered by cisplatin. Cisplatin‐treated neurons showed general transcription inhibition likely accounting for the reduced expression of the ERK1/2‐selective phosphatases including the dual specificity phosphatase‐6 (DUSP6) and the DUSP3 activator vaccinia‐related kinase‐3 (VRK3). Hence, cisplatin effects on ERK1/2 may be due to the deficient ERK1/2 inhibition by the transcription‐regulated phosphatases. Indeed, the transcription inhibitor actinomycin D reduced expression of DUSP6 and VRK3 while inducing the NMDAR‐dependent activation of ERK1/2 and the impairment of ERK1/2 dephosphorylation. Thus, cisplatin‐mediated transcriptional inhibition of ERK1/2 phosphatases contributed to delayed and long lasting accumulation of phospho‐ERK1/2 that was driven by the basal NMDAR activity. Our results provide the first direct evidence for transcriptionally‐regulated inactivation of neuronal ERK1/2. Its disruption likely contributes to neurodegeneration‐associated activation of ERK1/2.