Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death

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.

ACKNOWLEDGMENTS

The first two authors contributed equally to the work.

We thank A. Minden for the pJ5Ω-MEKK1Δ construct and S. Nagata for the rat FasL cDNA and Fas-Fc construct.

This work was supported by National Institutes of Health grants ES04151 and ES06376 (to M.K.) and CA69381 (to D.R.G.). H.L. was supported by the Lucille Markey Foundation and Molecular Endocrinology training grants. E.B. was supported by NIH grant GM52735 (to D.R.G.). Y.K. was supported by the Ministry of Education, Japanese Government, and F.-X.C. was supported by the French and Swiss Leagues against Cancer.