Dominant-Negative c-Jun Promotes Neuronal Survival by Reducing BIM Expression and Inhibiting Mitochondrial Cytochrome c Release

Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, WC1E 6BT, London, United Kingdom.
Neuron (Impact Factor: 15.05). 04/2001; 29(3):629-43. DOI: 10.1016/S0896-6273(01)00239-2
Source: PubMed


Sympathetic neurons require nerve growth factor for survival and die by apoptosis in its absence. Key steps in the death pathway include c-Jun activation, mitochondrial cytochrome c release, and caspase activation. Here, we show that neurons rescued from NGF withdrawal-induced apoptosis by expression of dominant-negative c-Jun do not release cytochrome c from their mitochondria. Furthermore, we find that the mRNA for BIM(EL), a proapoptotic BCL-2 family member, increases in level after NGF withdrawal and that this is reduced by dominant-negative c-Jun. Finally, overexpression of BIM(EL) in neurons induces cytochrome c redistribution and apoptosis in the presence of NGF, and neurons injected with Bim antisense oligonucleotides or isolated from Bim(-/-) knockout mice die more slowly after NGF withdrawal.


Available from: Jonathan Whitfield, Aug 27, 2014
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    • "However, p75 NTR alone may also promote survival and cell cycle progression by activating NF-κB (nuclear factor kappa-lightchain-enhancer of activated B cells) and Akt pathways when bound by neurotrophins (Hamanoue et al., 1999; Roux et al., 2001). With Sortilin as co-receptor (Nykjaer et al., 2004) and activated by proneurotrophins (Lee et al., 2001), p75 NTR induces apoptosis through JNK (c-Jun N-terminal kinase) induction (Harrington et al., 2002) and caspase activation through the mitochondrial apoptotic pathway (Whitfield et al., 2001; Harris and Johnson, 2001). Many signaling properties of p75 NTR are regulated by posttranslational modifications such as phosphorylation (Higuchi et al., 2003; Zhang et al., 2009), glycosylation (Yeaman et al., 1997; Breuza et al., 2002), and palmitoylation (Barker et al., 1994; Underwood et al., 2008). "
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    ABSTRACT: The p75 neurotrophin receptor (p75(NTR)) undergoes γ-secretase-mediated regulated intramembrane proteolysis and is involved in glioblastoma cell migration and invasion. Consistent with previous reports, in this study we show that p75NTR increases U87-MG glioblastoma cell migration, which is reversed by inhibition of γ-secretase activity. However, we show that expression or stabilization of the γ-secretase-generated p75(NTR) intracellular domain (ICD) is not sufficient to induce U87-MG glioblastoma cell migration, and that exogenous expression of p75(NTR) ICD inhibits p75(NTR)-mediated glioblastoma cell (U87-MG and U373-MG) migration. To identify pathways and to determine how p75(NTR) mediates glioblastoma migration we utilized a microarray approach to assess differential gene expression profiles between parental U87-MG and cells stably expressing wild-type p75(NTR), a γ-secretase cleavage-resistant chimeric p75(NTR) mutant (p75FasTM) and the γ-secretase-generated p75(NTR)-ICD, which mimics constitutively cleaved p75(NTR) receptor. In our microarray data analysis we identified a subset of genes that were constitutively up-regulated in wild-type p75(NTR) cells, which were also repressed in p75(NTR) ICD expressing cells. Furthermore, our data revealed amongst the many differentially expressed genes, cadherin-11 (Cdh-11), matrix metalloproteinase 12 and relaxin/insulin-like family peptide receptor 2 as constitutively up-regulated in wild-type p75(NTR) cells, independent of γ-secretase activity. Consistent with a role in glioblastoma migration, we found that U87-p75(NTR) cells express higher levels of Cdh-11 protein and that siRNA-mediated knockdown of Cdh-11 resulted in a significant decrease in p75(NTR)-mediated glioblastoma cell migration. Therefore, we hypothesize that p75(NTR) can impact U87-MG glioblastoma cell migration in a γ-secretase-independent manner through modulation of specific genes, including Cdh-11, and that both γ-secretase-independent and -dependent mechanisms are involved in p75(NTR)-mediated U87-MG glioblastoma cell migration.
    Molecular and Cellular Neuroscience 10/2015; 69. DOI:10.1016/j.mcn.2015.10.003 · 3.84 Impact Factor
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    • "Control and HDAC1/2-Ablated Retinae After Injury JNK is a member of the mitogen-activated protein kinase family (also known as the stress-activated protein kinases or SAPKs) that is activated in response to a variety of cellular stresses. Sustained activation contributes to cell death through different targets including c-Jun (Whitfield et al., 2001; Ma et al., 2007, p. 53; Fuchs et al., 1998a, 1998b) and Hrk (Chang et al., 2013). Previous studies have demonstrated that JNK signaling and its target transcription factor c-Jun are activated in RGCs following optic nerve injury. "
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    ABSTRACT: Histones deacetylases (HDACs), besides their function as epigenetic regulators, deacetylate and critically regulate the activity of nonhistone targets. In particular, HDACs control partially the proapoptotic activity of p53 by balancing its acetylation state. HDAC inhibitors have revealed neuroprotective properties in different models, but the exact mechanisms of action remain poorly understood. We have generated a conditional knockout mouse model targeting retinal ganglion cells (RGCs) to investigate specifically the functional role of HDAC1 and HDAC2 in an acute model of optic nerve injury. Our results demonstrate that combined HDAC1 and HDAC2 ablation promotes survival of axotomized RGCs. Based on global gene expression analyses, we identified the p53-PUMA apoptosis-inducing axis to be strongly activated in axotomized mouse RGCs. Specific HDAC1/2 ablation inhibited this apoptotic pathway by impairing the crucial acetylation status of p53 and reducing PUMA expression, thereby contributing to the ensuing enhanced neuroprotection due to HDAC1/2 depletion. HDAC1/2 inhibition and the affected downstream signaling components emerge as specific targets for developing therapeutic strategies in neuroprotection. © The Author(s) 2015.
    ASN Neuro 06/2015; 7(3). DOI:10.1177/1759091415593066 · 4.02 Impact Factor
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    • "Bcl-2 family members Bim and Puma have been implicated in previous studies examining mast cells apoptosis induced by cytokine withdrawal [8]. Additionally, Erk1/2 was shown to regulate expression of c-Jun, an established positive regulator of Bim expression [25]–[27]. We therefore asked whether the activation of the Erk1/2 pathway by PGE2 was paralleled by alteration in the expression of genes known in these pathways. "
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    ABSTRACT: Increased mast cell numbers are observed at sites of allergic inflammation and restoration of normal mast cell numbers is critical to the resolution of these responses. Early studies showed that cytokines protect mast cells from apoptosis, suggesting a simple model in which diminished cytokine levels during resolution leads to cell death. The report that prostaglandins can contribute both to recruitment and to the resolution of inflammation together with the demonstration that mast cells express all four PGE2 receptors raises the question of whether a single PGE2 receptor mediates the ability of PGE2 to regulate mast cell survival and apoptosis. We report here that PGE2 through the EP3 receptor promotes cell death of mast cells initiated by cytokine withdrawal. Furthermore, the ability of PGE2 to limit reconstitution of tissues with cultured mast cells is lost in cell lacking the EP3 receptor. Apoptosis is accompanied by higher dissipation of mitochondrial potential (ΔΨm), increased caspase-3 activation, chromatin condensation, and low molecular weight DNA cleavage. PGE2 augmented cell death is dependent on an increase in intracellular calcium release, calmodulin dependent kinase II and MAPK activation. Synergy between the EP3 pathway and the intrinsic mitochondrial apoptotic pathway results in increased Bim expression and higher sensitivity of mast cells to cytokine deprivation. This supports a model in which PGE2 can contribute to the resolution of inflammation in part by augmenting the removal of inflammatory cells in this case, mast cells.
    PLoS ONE 07/2014; 9(7):e102948. DOI:10.1371/journal.pone.0102948 · 3.23 Impact Factor
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