Mitogen‐activated protein kinase/extracellular signal‐regulated kinase attenuates 3‐hydroxykynurenine‐induced neuronal cell death

Lee, Hyun Jung; Bach, Jae Hyung; Chae, Hee Sun; Lee, Sang Hyung; Joo, Wan Seok; Choi, Se Hoon; Kim, Kyung Yong; Lee, Won Bok; Kim, Sung Su

doi:10.1111/j.1471-4159.2004.02191.x

Cited by 45 publications

(36 citation statements)

References 55 publications

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“…Mitochondrial ERK inhibition was reported to cause ATP depletion and apoptosis (6). In other studies, although the subcellular localization of ERK was not assessed, its inhibition prompted block of ATP synthase and mitochondrial depolarization (21,22). In this context, an important finding of this study is that an essential component of the mitochondrial death machinery, the PTP, is a downstream target of ERK.…”

Section: Discussionmentioning

confidence: 80%

Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

Rasola

Sciacovelli

Chiara

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

209

189

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We studied human cancer cell models in which we detected constitutive activation of ERK. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial permeability transition pore (PTP). PTP desensitization and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced glycogen synthase kinase-3 (GSK-3)-dependent phosphorylation of the pore regulator cyclophilin D, whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization was observed in nontransformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and cyclophilin D, a finding that provides a mechanistic basis for increased resistance to apoptosis of neoplastic cells.

show abstract

Section: Discussionmentioning

confidence: 80%

Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

Rasola

Sciacovelli

Chiara

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

209

189

View full text Add to dashboard Cite

show abstract

“…EGR-1, a zinc finger transcription factor, has been implicated in diverse biological functions, including cell growth, differentiation (28,29), and apoptosis (30 -32). In cerebellar granule cells, the EGR-1 family of transcription factors plays a critical role in apoptosis by facilitating c-Jun activation (31).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of Glycogen Synthase Kinase-3 Isoforms in the Regulation of Transcriptional Activation

Liang

Chuang

2006

Journal of Biological Chemistry

119

110

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Glycogen synthase kinase-3 (GSK-3) exists as two structurally similar isoforms, ␣ and ␤, whose activities are negatively regulated by serine phosphorylation but positively controlled by tyrosine phosphorylation. We used GSK-3 isoform-specific small interfering RNAs, dominant negative mutants, and pharmacological inhibitors to search for the differential roles for both GSK-3 isoforms in regulating transcriptional activation in cultured rat cerebral cortical neurons. GSK-3␣ and GSK-3␤ were shown to have differentially regulated transactivation such that GSK-3␣ silencing/inhibition was more robust than GSK-3␤ silencing/inhibition in causing cAMP-responsive element-and NF-B-dependent transactivation. Moreover, protein-DNA array studies identified two novel GSK-3-regulated transcription factors, early growth response 1 and Smad3/4, which were oppositely affected by GSK-3␣ or GSK-3␤ silencing or inhibition. Taken together, our results underscore critical variations in the function and regulation of GSK-3␣ and GSK-3␤. The development of GSK-3 isoform-specific inhibitors is thus crucial for therapeutic intervention of GSK-3-related neuropathological conditions.

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“…Activation of the ERKs themselves by fructose-1,6-bisphosphate has also been shown to protect against neuronal death caused by hypoxia (Fahlman et al, 2002). These protective effects of the ERKs appear to occur via the maintenance of mitochondrial function (Lee et al, 2004).…”

Section: Hypothetical Mechanisms For Npy Neuroprotective Actionsmentioning

confidence: 99%

Neuropeptide Y Protects against Methamphetamine-Induced Neuronal Apoptosis in the Mouse Striatum

Thiriet¹,

Deng²,

Solinas³

et al. 2005

J. Neurosci.

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Methamphetamine (METH) is an illicit drug that causes neuronal apoptosis in the mouse striatum, in a manner similar to the neuronal loss observed in neurodegenerative diseases. In the present study, injections of METH to mice were found to cause the death of enkephalin-positive projection neurons but not the death of neuropeptide Y (NPY)/nitric oxide synthase-positive striatal interneurons. In addition, these METH injections were associated with increased expression of neuropeptide Y mRNA and changes in the expression of the NPY receptors Y 1 and Y 2 . Administration of NPY in the cerebral ventricles blocked METH-induced apoptosis, an effect that was mediated mainly by stimulation of NPY Y 2 receptors and, to a lesser extent, of NPY Y 1 receptors. Finally, we also found that neuropeptide Y knock-out mice were more sensitive than wild-type mice to METH-induced neuronal apoptosis of both enkephalin-and nitric oxide synthase-containing neurons, suggesting that NPY plays a general neuroprotective role within the striatum. Together, our results demonstrate that neuropeptide Y belongs to the class of factors that maintain neuronal integrity during cellular stresses. Given the similarity between the cell death patterns induced by METH and by disorders such as Huntington's disease, our results suggest that NPY analogs might be useful therapeutic agents against some neurodegenerative processes.

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Mitogen‐activated protein kinase/extracellular signal‐regulated kinase attenuates 3‐hydroxykynurenine‐induced neuronal cell death

Cited by 45 publications

References 55 publications

Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

Differential Roles of Glycogen Synthase Kinase-3 Isoforms in the Regulation of Transcriptional Activation

Neuropeptide Y Protects against Methamphetamine-Induced Neuronal Apoptosis in the Mouse Striatum

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