Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases.
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.
Gozdz
Agata
A
Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, Louisville, Kentucky 40292, USA.
Vashishta
Aruna
A
Kalita
Katarzyna
K
Szatmari
Erzsebet
E
Zheng
Jing-Juan
JJ
Tamiya
Shigeo
S
Delamere
Nicholas A
NA
Hetman
Michal
M
D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000633:toxicity; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D054642:Dual Specificity Phosphatase 6 / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D017346:Protein Serine-Threonine Kinases; C527264:VRK3 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054642:Dual Specificity Phosphatase 6; C517037:Dusp6 protein, rat; D002945:Cisplatin