PMID- 18665890 OWN - NLM STAT- MEDLINE DCOM- 20081103 LR - 20211203 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 106 IP - 5 DP - 2008 Sep TI - Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases. PG - 2056-67 LID - 10.1111/j.1471-4159.2008.05550.x [doi] AB - 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. FAU - Gozdz, Agata AU - Gozdz A AD - Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, Louisville, Kentucky 40292, USA. FAU - Vashishta, Aruna AU - Vashishta A FAU - Kalita, Katarzyna AU - Kalita K FAU - Szatmari, Erzsebet AU - Szatmari E FAU - Zheng, Jing-Juan AU - Zheng JJ FAU - Tamiya, Shigeo AU - Tamiya S FAU - Delamere, Nicholas A AU - Delamere NA FAU - Hetman, Michal AU - Hetman M LA - eng GR - P20 RR015576/RR/NCRR NIH HHS/United States GR - R01 NS047341-01A1/NS/NINDS NIH HHS/United States GR - R01 NS047341/NS/NINDS NIH HHS/United States GR - P20 RR015576-050005/RR/NCRR NIH HHS/United States GR - RR015576-06/RR/NCRR NIH HHS/United States GR - NS047341-01/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080704 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Antineoplastic Agents) RN - 0 (Enzyme Inhibitors) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (VRK3 protein, rat) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.1.3.16 (Mitogen-Activated Protein Kinase Phosphatases) RN - EC 3.1.3.48 (Dual Specificity Phosphatase 6) RN - EC 3.1.3.48 (Dusp6 protein, rat) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Animals MH - Animals, Newborn MH - Antineoplastic Agents/toxicity MH - Cells, Cultured MH - Cisplatin/*toxicity MH - Dual Specificity Phosphatase 6/drug effects/metabolism MH - Enzyme Activation/drug effects/genetics MH - Enzyme Inhibitors/toxicity MH - Gene Expression Regulation, Enzymologic/drug effects/genetics MH - Mitogen-Activated Protein Kinase 1/drug effects/genetics/metabolism MH - Mitogen-Activated Protein Kinase 3/*drug effects/genetics/metabolism MH - Mitogen-Activated Protein Kinase Phosphatases/*antagonists & inhibitors/genetics/metabolism MH - Nerve Degeneration/*chemically induced/*enzymology/physiopathology MH - Neurons/drug effects/enzymology MH - Phosphorylation/drug effects MH - Protein Serine-Threonine Kinases/drug effects/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/drug effects/metabolism MH - Transcriptional Activation/drug effects/*genetics PMC - PMC2574929 MID - NIHMS64289 EDAT- 2008/07/31 09:00 MHDA- 2008/11/04 09:00 PMCR- 2009/09/01 CRDT- 2008/07/31 09:00 PHST- 2008/07/31 09:00 [pubmed] PHST- 2008/11/04 09:00 [medline] PHST- 2008/07/31 09:00 [entrez] PHST- 2009/09/01 00:00 [pmc-release] AID - JNC5550 [pii] AID - 10.1111/j.1471-4159.2008.05550.x [doi] PST - ppublish SO - J Neurochem. 2008 Sep;106(5):2056-67. doi: 10.1111/j.1471-4159.2008.05550.x. Epub 2008 Jul 4.