Dual Roles for c-Jun N-Terminal Kinase in Developmental and Stress Responses in Cerebellar Granule Neurons

Coffey, Eleanor T.; Hongisto, Vesa; Dickens, Martin; Davis, Roger J.; Courtney, Michael J.

doi:10.1523/jneurosci.20-20-07602.2000

Cited by 182 publications

(207 citation statements)

References 73 publications

(92 reference statements)

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“…07-194; see Materials and Methods). We repeated this experiment using a second antibody (from Santa-Cruz, see Coffey et al 26 ), but were still not able to detect an increase of MKK4 in the nuclei after NMDA stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…Samples were then centrifuged at 900 Â g for 10 min at 41C to separate the supernatants (cytoplasmic fractions) from the pellets (nuclear fractions). 26 Nuclear pellets were washed once in the lysis buffer and centrifuged at 900 Â g for 5 min at 41C, after which the pellets were reconstituted in lysis buffer and sonicated. Samples were analyzed for protein determination and equal proportions of nuclear and cytoplasmic fractions were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).…”

Section: Discussionmentioning

confidence: 99%

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Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons

et al. 2006

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Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the Dretro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4) In many nervous system disorders, including cerebral ischemia, traumatic brain injury and neurodegenerative diseases, overactivation of N-methyl-d-aspartate (NMDA) receptors leads to neuronal damage, resulting in neuronal loss and consequent severe neurological impairment. This cascade of neuronal injury, referred to as 'excitotoxicity', is still only partly understood. Dying neurons activate complex signal transduction events to trigger their death program, and the c-Jun N-terminal kinase (JNK) pathway plays an important role in this process. 1 D-retro-inverso form of JNK inhibitor (D-JNKI1) is an extremely potent neuroprotectant against excitotoxicity of cortical neurons and against different in vivo paradigms of neurodegeneration. [2][3][4] The active part of this peptide contains a retro-inverso form of a 20-amino-acid sequence (JBD 20 ) from the JNK-binding domain (JBD) of the scaffold protein JNK-interacting protein-1 (IB1/JIP-1), and it blocks the access of JNK to many of its targets. [5][6][7] Recently, Negri et al. 8,9 performed a detailed re-examination of the JBD-containing proteins and identified 19 different substrates of JNK. They then proved in a cell-free assay that the JBD 20 sequence prevented interactions and phosphorylations by JNK of nine of these targets. Among these nine substrates, we have studied the following four that might participate in regulating the death of cortical neurons: (1) MADD/DENN (MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells); (2-3) mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), the two direct upstream activators of JNK and (4) the scaffold protein IB1/JIP-1.,In particularly, MADD/DENN was identified as a substrate for JNK3, 10 the isoform most clearly involved in excitotoxicity 11,12 and mostly expressed in the brain. [10][11][12] Increasing evidence supports a strong correlation between low MADD/ DENN expression and neuronal loss. 13,14 MKK4 and MKK7 are the only known JNK activators. In some cell types, MKK4 activates JNK primarily by stress stimuli and MKK7 by inflammatory cytoki...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons

et al. 2006

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“…JNK proteins are a subset of MAP kinase signalling molecules well-known for their role in the apoptotic process in the nervous system (Brecht et al 2005;Kuan et al 1999;Yang et al 1997), but also recognised for their role in neuronal differentiation (Coffey et al 2000;Waetzig and Herdegen 2003). There are three known JNK proteins (JNKs 1, 2 and 3) with a total of ten isoforms, all of which are expressed in the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…JNK3 is best known for its role in apoptosis, but recent data point to a relevant function in neuronal differentiation and brain development (Coffey et al 2000;Neidhart et al 2001;Waetzig and Herdegen 2003), which may be relevant for understanding the mechanism by which a truncated JNK3 protein could lead to the severe encephalopathy phenotype observed in the patient.…”

Section: Introductionmentioning

confidence: 99%

Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy

et al. 2005

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We have investigated the breakpoints in a male child with pharmacoresistant epileptic encephalopathy and a de novo balanced translocation t(Y;4)(q11.2;q21). By fluorescence in situ hybridisation, we have identified genomic clones from both chromosome 4 and chromosome Y that span the breakpoints. Precise mapping of the chromosome 4 breakpoint indicated that the c-Jun N-terminal kinase 3 (JNK3) gene is disrupted in the patient. This gene is predominantly expressed in the central nervous system, and it plays an established role in both neuronal differentiation and apoptosis. Expression studies in the patient lymphoblastoid cell line show that the truncated JNK3 protein is expressed, i.e. the disrupted transcript is not immediately subject to nonsense-mediated mRNA decay, as is often the case for truncated mRNAs or those harbouring premature termination codons. Over-expression studies with the mutant protein in various cell lines, including neural cells, indicate that both its solubility and cellular localisation differ from that of the wild-type JNK3. It is plausible, therefore, that the presence of the truncated JNK3 disrupts normal JNK3 signal transduction in neuronal cells. JNK3 is one of the downstream effectors of the GTPase-regulated MAP kinase cascade, several members of which have been implicated in cognitive function. In addition, two known JNK3-interacting proteins, barrestin 2 and JIP3, play established roles in neurite outgrowth and neurological development. These interactions are likely affected by a truncated JNK3 protein, and thereby provide an explanation for the link between alterations in MAP kinase signal transduction and brain disorders.

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“…JNK activation and nuclear translocation in neurons have been reported in vivo under different pathological conditions. Nuclear localization of JNK has been detected in degenerating neurons of Alzheimer patients (Zhu et al, 2001) and in cerebellar granule neurons (Coffey et al, 2000(Coffey et al, , 2002. JNK1 and JNK3 translocation from the cytosol to the nucleus in neurons can also be observed in experimental models of hypoxia (Zhang et al, 1998) and ischemia (Mizukami et al, 1997) respectively.…”

Section: Discussionmentioning

confidence: 99%