Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death

Helen Le-Niculescu, Emanuela Bonfoco, Yoshitoshi Kasuya, Francois Xavier Claret, Douglas R. Green, Michael Karin

Research output: Contribution to journalArticle

434 Citations (Scopus)

Abstract

The JNK pathway modulates AP-1 activity. While in some cells it may have proliferative and protective roles, in neuronal cells it is involved in apoptosis in response to stress or withdrawal of survival signals. To understand how JNK activation leads to apoptosis, we used PC12 cells and primary neuronal cultures. In PC12 cells, deliberate JNK activation is followed by induction of Fas ligand (FasL) expression and apoptosis. JNK activation detected by c-Jun phosphorylation and FasL induction are also observed after removal of either nerve growth factor from differentiated PC12 cells or KCl from primary cerebellar granule neurons (CGCs). Sequestation of FasL by incubation with a Fas-Fc decoy inhibits apoptosis in all three cases. CGCs derived from gld mice (defective in FasL) are less sensitive to apoptosis caused by KCl removal than wild-type neurons. In PC12 cells, protection is also conferred by a c-Jun mutant lacking JNK phosphoacceptor sites and a small molecule inhibitor of p38 mitogen-activated protein kinase and JNK, which inhibits FasL induction. Hence, the JNK-to-c-Jun-to-FasL pathway is an important mediator of stress-induced neuronal apoptosis.

Original languageEnglish (US)
Pages (from-to)751-763
Number of pages13
JournalMolecular and Cellular Biology
Volume19
Issue number1
StatePublished - Jan 1999
Externally publishedYes

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Fas Ligand Protein
MAP Kinase Signaling System
Cell Death
PC12 Cells
Apoptosis
Neurons
Cytoprotection
Transcription Factor AP-1
Nerve Growth Factor
p38 Mitogen-Activated Protein Kinases
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death. / Le-Niculescu, Helen; Bonfoco, Emanuela; Kasuya, Yoshitoshi; Claret, Francois Xavier; Green, Douglas R.; Karin, Michael.

In: Molecular and Cellular Biology, Vol. 19, No. 1, 01.1999, p. 751-763.

Research output: Contribution to journalArticle

Le-Niculescu, Helen ; Bonfoco, Emanuela ; Kasuya, Yoshitoshi ; Claret, Francois Xavier ; Green, Douglas R. ; Karin, Michael. / Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death. In: Molecular and Cellular Biology. 1999 ; Vol. 19, No. 1. pp. 751-763.
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