Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release

Neuron. 2001 Mar;29(3):629-43. doi: 10.1016/s0896-6273(01)00239-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology
  • Caspases / metabolism
  • Cell Survival*
  • Cells, Cultured
  • Cytochrome c Group / metabolism*
  • Enzyme Activation
  • Gene Expression
  • MAP Kinase Kinase Kinase 1*
  • Membrane Proteins*
  • Mice
  • Mice, Knockout
  • Microinjections
  • Mitochondria / metabolism*
  • Nerve Growth Factor / administration & dosage
  • Nerve Growth Factor / physiology
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Oligonucleotides, Antisense / pharmacology
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / physiology*
  • Proto-Oncogene Proteins*
  • Rats
  • Rats, Sprague-Dawley
  • Superior Cervical Ganglion / cytology
  • Transfection

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bcl2l11 protein, rat
  • Carrier Proteins
  • Cytochrome c Group
  • Membrane Proteins
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-jun
  • Nerve Growth Factor
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinase 1
  • Map3k1 protein, mouse
  • Caspases