Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases

Agata Gozdz, Aruna Vashishta, Katarzyna Kalita, Erzsebet Szatmari, Jing Juan Zheng, Shigeo Tamiya, Nicholas A Delamere, Michal Hetman

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2056-2067
Number of pages12
JournalJournal of Neurochemistry
Volume106
Issue number5
DOIs
StatePublished - Sep 2008

Fingerprint

Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Phosphoric Monoester Hydrolases
Cisplatin
Chemical activation
N-Methyl-D-Aspartate Receptors
Dual Specificity Phosphatase 6
Transcription
Vaccinia
Phosphorylation
Neurons
Phosphotransferases
Dactinomycin
Rats

Keywords

  • DNA damage
  • Mitogen-activated protein kinase
  • NMDA receptor
  • Phosphatases
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases. / Gozdz, Agata; Vashishta, Aruna; Kalita, Katarzyna; Szatmari, Erzsebet; Zheng, Jing Juan; Tamiya, Shigeo; Delamere, Nicholas A; Hetman, Michal.

In: Journal of Neurochemistry, Vol. 106, No. 5, 09.2008, p. 2056-2067.

Research output: Contribution to journalArticle

Gozdz, Agata ; Vashishta, Aruna ; Kalita, Katarzyna ; Szatmari, Erzsebet ; Zheng, Jing Juan ; Tamiya, Shigeo ; Delamere, Nicholas A ; Hetman, Michal. / Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases. In: Journal of Neurochemistry. 2008 ; Vol. 106, No. 5. pp. 2056-2067.
@article{92d16f4b57f1400fa0a578167ce02ced,
title = "Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases",
abstract = "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.",
keywords = "DNA damage, Mitogen-activated protein kinase, NMDA receptor, Phosphatases, Transcription",
author = "Agata Gozdz and Aruna Vashishta and Katarzyna Kalita and Erzsebet Szatmari and Zheng, {Jing Juan} and Shigeo Tamiya and Delamere, {Nicholas A} and Michal Hetman",
year = "2008",
month = "9",
doi = "10.1111/j.1471-4159.2008.05550.x",
language = "English (US)",
volume = "106",
pages = "2056--2067",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases

AU - Gozdz, Agata

AU - Vashishta, Aruna

AU - Kalita, Katarzyna

AU - Szatmari, Erzsebet

AU - Zheng, Jing Juan

AU - Tamiya, Shigeo

AU - Delamere, Nicholas A

AU - Hetman, Michal

PY - 2008/9

Y1 - 2008/9

N2 - 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.

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.

KW - DNA damage

KW - Mitogen-activated protein kinase

KW - NMDA receptor

KW - Phosphatases

KW - Transcription

UR - http://www.scopus.com/inward/record.url?scp=49549100904&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49549100904&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2008.05550.x

DO - 10.1111/j.1471-4159.2008.05550.x

M3 - Article

VL - 106

SP - 2056

EP - 2067

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 5

ER -