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

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
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.

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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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    • "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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    • "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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