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

Abstract

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.

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…These findings were supported by observations in mice with a mutation in the c-Jun gene that altered the JNK phosphorylation sites of c-Jun and led to a resistance against kainic acid triggered death of hippocampal neurons [15]. Further support arose from data obtained using dominant-negative c-Jun mutants, which reduced sympathetic neuronal death following NGF withdrawal [214]. A pro-apoptotic function has also been suggested for JNK activation in NGFwithdrawal-induced neuronal death [59] in a hippocampal model of Huntington's disease [124] and in beta-amyloidinduced neuronal apoptosis [204].…”

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

“…Although Bim can be regulated on the level of expression (Dijkers et al, 2000;Putcha et al, 2001;Whitfield et al, 2001), many healthy cells and tissues express easily detectable levels of Bim (O'Reilly et al, 2000). In these cells, Bim is probably kept inactive by sequestration to the dynein motor complex on microtubules and activated by its release through an unknown mechanism (Puthalakath et al, 1999).…”

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

“…BH3-only proteins induce apoptosis by activating the pro-apoptotic Bcl-2 family members, Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), and by antagonizing anti-apoptotic members such as Bcl-2 and induced myeloid leukemia cell differentiation protein 1. 1 The Bcl-2-interacting mediator of cell death (Bim) protein is a BH3-only member of the Bcl-2 family that is an important initiator of apoptosis in lymphocytes in response to growth factor withdrawal [2][3][4] and elimination of autoreactive T cells in the thymus. 5 Deletion of a single allele of Bim can accelerate the progression of lymphomas in the Em-myc model, suggesting the apoptotic activity of Bim has tumor-suppressor activity in vivo.…”

“…At the transcriptional level, the promoter of the Bim gene is activated by stress-inducible transcription factors including activator protein 1 and forkhead box protein O. 4,7,8 Post-transcriptional mechanisms that have been shown to control Bim expression levels include both mRNA stability 9 and protein stability. [10][11][12] Signaling downstream of receptor tyrosine kinases (RTKs) including epidermal growth factor receptor induce the proteasomal degradation of Bim.…”