Targeting JNK3 for the treatment of neurodegenerative disorders

Resnick, Lauren B.; Fennell, Myles

doi:10.1016/s1359-6446(04)03251-9

Cited by 116 publications

(87 citation statements)

References 38 publications

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“…5,6 Moreover, c-Jun phosphorylation has been associated with neuronal apoptosis in several neuro-pathological conditions including neuro-degenerative disorders. 7,8 These findings, together with others, have implied an important role for the JNK/c-Jun pathway in regulating several cellular processes.…”

mentioning

confidence: 62%

c-Jun promotes cellular survival by suppression of PTEN

et al. 2006

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mentioning

confidence: 62%

c-Jun promotes cellular survival by suppression of PTEN

et al. 2006

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“…Here, we characterize the participation of eNOS in the regulation of SDF-1␣-mediated endothelial cell activation. We demonstrate that JNK3, which has previously been predominantly linked to neuronal signaling (18), is expressed in endothelial cells and is a key mediator of eNOS-dependent SDF-1␣-induced endothelial cell migratory responses. MAPK phosphatase 7 (MKP7) (or DUSP16), a JNK3 phosphatase that binds to the JNK3 adaptor protein ␤-arrestin2, is a critical link in this eNOS-dependent JNK3 activation, undergoing nitrosylation and enzymatic inhibition after SDF-1␣ administration.…”

mentioning

confidence: 71%

SDF-1α stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration

Wu²,

Ferguson³

et al. 2009

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

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The chemokine stromal cell-derived factor-1␣ (SDF-1␣) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and endothelial cell migration, yet very little is known about the actual signaling events that mediate SDF-1␣-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1␣-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1␣-induced activation of JNK3, critical for endothelial cell migration, depends on the prior activation of eNOS. Specifically, activation of eNOS leads to production of NO and subsequent nitrosylation of MKP7, rendering the phosphatase inactive and unable to inhibit the activation of JNK3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for SDF-1␣-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.

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“…Taken together, our results indicate that JNK3 is the primary target of HDRP-mediated neuroprotection. It is noteworthy that the loss of JNK3 protects mice against neuronal loss induced by axotomy, ischemic stroke, and glutamate-induced excitotoxicity (21,34,46). In contrast, the loss of either JNK1 or JNK2 alone has no serious consequences.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Histone Deacetylase-Related Protein

Morrison

Majdzadeh

Zhang

et al. 2006

Molecular and Cellular Biology

156

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Apoptosis is an essential aspect of normal nervous system development, but when aberrantly activated, apoptosis leads to undesirable neuronal death, and such inappropriate neuronal loss is the hallmark of a variety of neurodegenerative diseases and neurological conditions, such as stroke or traumatic brain injury. The mechanisms underlying the regulation of apoptosis are beginning to be understood. Among the molecules that have recently been implicated are the histone deacetylases (HDACs). HDACs are the catalytic subunits of multiprotein complexes that deacetylate histones (11,42). The action of HDACs is opposed by histone acetyltransferases (HATs) such as CREB-binding protein and p300, which catalyze the transfer of an acetyl moiety from acetyl-coenzyme A to specific lysine residues of histones (25). Acetylation of histones relaxes the chromatin structure to a state that is transcriptionally active, while histone deacetylation transforms chromatin to a transcriptionally repressed state (25). Hence, gene expression is regulated, in part, by the balance of HDAC and HAT activities. Although best studied for their effects on histones and transcriptional activity, it is now known that HDACs and HATs regulate the acetylation of a number of other nonhistone proteins, such as p53, p65/RelA, E2F1, GATA1, and MyoD, suggesting complex functions of HDACs in different cellular processes (11,42). Precisely which cellular functions are involved is currently the subject of intense investigation.Vertebrates express at least 18 distinct HDACs, which have been grouped into three classes based on their similarities with Saccharomyces cerevisiae HDACs (11,42 Class I HDACs consist of little more than a deacetylase domain and function as transcriptional repressors. They generally are nuclear proteins expressed in most tissue and cell types (11,42). On the other hand, members of the class II HDAC subfamily display cell type-restricted patterns of expression and contain a large extended N-terminal extension with which a variety of signaling proteins interact, including MEF2, HP1␣, Bcl6, CtBP, calmodulin,42). Phosphorylation of conserved serine residues in class II HDACs by calcium/calmodulin-dependent kinase (CaMK) or protein kinase D in response to specific stimuli creates docking sites for the 14-3-3 family of protein chaperones (11,28,31,42). Binding of 14-3-3 results in the export of these HDACs from the nucleus and disrupts their interactions with transcriptional corepressor proteins, resulting in derepression of their target genes.Several classes of small-molecule HDAC inhibitors have been identified (11,29 (11,29). Because of their ability to induce the death of transformed cells, HDAC inhibitors are in clinical trials for the treatment of cancers. It is noteworthy, however, that while there are small differences in the sensitivities of individual class I and class II HDACs to different inhibitors, most of the commonly used inhibitors inhibit all HDACs efficiently. The significance of individual HDACs in any biological effect ha...

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Targeting JNK3 for the treatment of neurodegenerative disorders

Cited by 116 publications

References 38 publications

c-Jun promotes cellular survival by suppression of PTEN

c-Jun promotes cellular survival by suppression of PTEN

SDF-1α stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration

Neuroprotection by Histone Deacetylase-Related Protein

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