Proapoptotic Nix Activates the JNK Pathway by Interacting with POSH and Mediates Death in a Parkinson Disease Model

Wilhelm, Michael; Xu, Zhiheng; Kukekov, Nickolay V.; Gire, Stephen; Greene, Lloyd A.

doi:10.1074/jbc.m607038200

Cited by 35 publications

(22 citation statements)

References 30 publications

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“…Interaction between a scaffold protein plenty of SH3 domains (POSH) and Nix (a pro-apoptotic BH3-only protein) has been found to effect JNK activation and apoptosis by a mechanism dependent on mutual stabilization [85] . In a cellular model of Parkinson ' s, reliant on exposure of PC12 cells to 6-hydroxydopamine, overexpression of Nix was found to mediate apoptosis.…”

Section: Neurologymentioning

confidence: 99%

c-Jun N-terminal kinases as potential therapeutic targets

Salh

2007

Expert Opinion on Therapeutic Targets

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One principal aim of research in the signal transduction field is to identify targets for therapeutic intervention, in an attempt to modify disease and curtail human suffering. Diseases such as chronic inflammation, atherosclerosis, diabetes and cancer exact a huge toll on health, in physical, social and financial terms. Defective signaling mechanisms are central to their pathogenesis. One candidate signaling molecule that is presently undergoing intense investigation is the c-Jun N-terminal kinase. With roles described in almost all classes of disease, the main questions are what type of inhibitor to use and when exactly to use it during the disease course?

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Section: Neurologymentioning

confidence: 99%

c-Jun N-terminal kinases as potential therapeutic targets

Salh

2007

Expert Opinion on Therapeutic Targets

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“…POSH and Sh3rf2 were used for in vitro transcription and translation using the TNT-coupled reticulocyte lysate system (Promega, Madison, WI). Incubation, washing, and resolution of radiolabeled proteins was performed as previously described (27).…”

Section: Methodsmentioning

confidence: 99%

“…For these experiments we utilized HEK293 cells that constitutively express siRNA targeting POSH (siPOSH cells) and that consequently have significantly reduced expression of endogenous POSH (27). We examined wild-type (WT) and siPOSH cells transfected with sihuSh3rf2 or a scrambled siRNA for JNK and c-Jun activation.…”

Section: Sh3rf2mentioning

confidence: 99%

Sh3rf2/POSHER Protein Promotes Cell Survival by Ring-mediated Proteasomal Degradation of the c-Jun N-terminal Kinase Scaffold POSH (Plenty of SH3s) Protein

Wilhelm

Kukekov

Schmit

et al. 2012

Journal of Biological Chemistry

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Background: Scaffold proteins, such as the pro-apoptotic scaffold POSH (Plenty of SH3s), organize MAP kinase pathways into functional modules. Results: Sh3rf2 promotes the degradation of POSH and prevents apoptosis in multiple cell types. Conclusion: Sh3rf2 antagonizes POSH-JNK signaling under basal conditions and provides a "brake" on apoptosis. Significance: Sh3rf2 may provide a target in neoplasia and apoptosis involving POSH such as trophic factor deprivation.

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“…JNKs are members of the mitogen-activated protein kinase (MAPK) pathway that is activated in response to many extracellular stimuli and different forms of environmental stress. JNK participates in intracellular signaling pathways mediating transmission of signals from the plasma membrane to the nucleus and is critically involved in the apoptosis after 6-OHDA injury in vitro (Jiang et al, 2004;Ouyang and Shen, 2006;Wilhelm et al, 2007). JNK1 and JNK2 have a broad tissue distribution, whereas JNK3 seems to be primarily to be localized in neuronal tissues and the cardiac myocytes (Mohit et al,1995).…”

mentioning

confidence: 99%

“…MLK3, an intracellular serine/threonine kinase, has been identified as a novel upstream activator of the JNK pathway (Gallo et al, 2002;Zhang and Zhang, 2005). At the same time, ASK1 is also considered to play a critical role in dopamine-induced apoptosis through activation of JNK in vitro (Jiang et al, 2004;Ouyang and Shen, 2006;Wilhelm et al, 2007). Both of them function as an mitogen-activated protein kinase kinase kinase of the JNK stress pathway by directly phosphorylating and activating the JNK activators such as stress-activated protein kinase/Erk kinase-1/MAPK kinase 4 and MAPK kinase 7 (MKK7).…”

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confidence: 99%

K252a Prevents Nigral Dopaminergic Cell Death Induced by 6-Hydroxydopamine through Inhibition of Both Mixed-Lineage Kinase 3/c-Jun NH2-Terminal Kinase 3 (JNK3) and Apoptosis-Inducing Kinase 1/JNK3 Signaling Pathways

Pan

Wang²,

Yang³

et al. 2007

Molecular Pharmacology

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It is well documented that the mitogen-activated protein kinase pathway plays a pivotal role in rats with 6-hydroxydopamine (6-OHDA)-induced unilateral lesion in the nigrostriatal system. Our recent studies have shown that mixed-lineage kinase 3 (MLK3) and apoptosis-inducing kinase 1 (ASK1) are all involved in neuronal cell death induced by ischemia, which is mediated by the MLK3/ c-Jun NH 2 -terminal kinase 3 (JNK3) and ASK1/ JNK signaling pathway. To investigate whether these pathways are correlated with 6-OHDA-induced lesion as well, we examined the phosphorylation of MLK3, ASK1, and JNK3 in 6-OHDA rats. The results showed that both MLK3 and ASK1 could activate JNK3 and then subsequently enhance the neuronal death through its downstream pathways (i.e., nuclear and nonnuclear pathway). K252a have wide-range effects including Trk inhibition, MLK3 inhibition, and activation of phosphatidylinositol 3 kinase and mitogen-activated protein kinase kinase signaling pathways through interactions with distinct targets and is a well known neuroprotective compound. We found that K252a could protect dopaminergic neurons against cell program death induced by 6-OHDA lesion, and the phenotypes of 6-OHDA rat model treated with K252a were partial rescued. The inhibition of K252a on the activation of MLK3/JNK3 and ASK1/JNK3 provided a link between 6-OHDA lesion and stress-activated kinases. It suggested that both proapoptotic MLK3/JNK3 and ASK1/JNK3 cascade may play an important role in dopaminergic neuronal death in 6-OHDA insult. Thus, the JNK3 signaling may eventually emerge as a prime target for novel therapeutic approaches to treatment of Parkinson disease, and K252a may serve as a potential and important neuroprotectant in therapeutic aspect in Parkinson disease.Although the expression of a number of cell death regulatory genes and receptors have been investigated in the 6-OHDA lesion model, the exact molecular mechanisms of programed cell death underlying neurodegeneration remain poorly understood. The aim of recent studies has been set to identify the key components of the cell death machinery in dopaminergic neurons and to understand how intracellular signaling pathways regulate programmed cell death.The key components of the neuronal death machinery include mitogen-activated protein kinase kinase kinase, such as mixed-lineage kinase 3 (MLK3) or apoptosis signal-regulated kinase1 (ASK1), mitogen-activated protein kinase kinase, c-Jun N-terminal protein kinases (JNKs), and its down-

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Proapoptotic Nix Activates the JNK Pathway by Interacting with POSH and Mediates Death in a Parkinson Disease Model

Cited by 35 publications

References 30 publications

c-Jun N-terminal kinases as potential therapeutic targets

c-Jun N-terminal kinases as potential therapeutic targets

Sh3rf2/POSHER Protein Promotes Cell Survival by Ring-mediated Proteasomal Degradation of the c-Jun N-terminal Kinase Scaffold POSH (Plenty of SH3s) Protein

K252a Prevents Nigral Dopaminergic Cell Death Induced by 6-Hydroxydopamine through Inhibition of Both Mixed-Lineage Kinase 3/c-Jun NH2-Terminal Kinase 3 (JNK3) and Apoptosis-Inducing Kinase 1/JNK3 Signaling Pathways

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