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Pin1 promotes cell death in NGF-dependent neurons through a mechanism requiring c-Jun activity

Maria Cecilia Barone1, Lynette A Desouza, Robert S Freeman

  • 1Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, New York, USA.

Journal of Neurochemistry
|April 19, 2008
PubMed

Insights

The prolyl isomerase Pin1 promotes neuronal death by increasing phosphorylated c-Jun levels. Inhibiting Pin1 protects developing neurons from apoptosis, suggesting a novel cell death pathway.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Death Research

Background:

  • Developing neurons undergo apoptosis when deprived of trophic support, involving pathways like JNK, c-Jun, Bim, and caspases.
  • The precise regulatory mechanisms governing these neuronal death pathways remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the prolyl isomerase Pin1 in regulating neuronal apoptosis.
  • To elucidate the mechanism by which Pin1 influences cell death pathways, particularly involving c-Jun.

Main Methods:

  • Utilized nerve growth factor (NGF)-maintained neuronal cultures.
  • Manipulated Pin1 levels through ectopic expression and knockdown.
  • Assessed neuronal death, c-Jun phosphorylation (Ser63), Bax dependency, cytochrome c release, and caspase activation.
  • Compared effects in wild-type and Bim knockout neurons.
  • Employed dominant-negative c-Jun to block Pin1-induced death.

Main Results:

  • Ectopic Pin1 induced caspase-dependent neuronal death, associated with increased Ser(63)-phosphorylated c-Jun and partial Bax dependency.
  • Pin1 knockdown prior to NGF withdrawal reduced c-Jun phosphorylation, inhibited cytochrome c release, and delayed cell death.
  • Pin1 knockdown provided significant protection, comparable to dominant-negative c-Jun, and was effective in both Bim(+/+) and Bim(-/-) neurons.
  • Ectopic Pin1-induced cell death was largely blocked by dominant-negative c-Jun.

Conclusions:

  • Pin1 acts as a positive regulator of neuronal death through a c-Jun-dependent mechanism.
  • Pin1 promotes cell death by increasing the accumulation of phosphorylated c-Jun.
  • This study reveals a novel pathway where Pin1 activation contributes to neuronal apoptosis.

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