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

The JNK pathway modulates AP-1 activity. While in some cells it may have pr oliferative and protective roles, in neuronal cells it is involved in apopt osis in response to stress or withdrawal of survival signals. To understand how JNK activation leads to apoptosis, we used PC12 cells and primary neur onal cultures. In PC12 cells, deliberate JNK activation is followed by indu ction of Fas ligand (FasL) expression and apoptosis. JNK activation detecte d by c-Jun phosphorylation and Fast induction are also observed after remov al of either nerve growth factor from differentiated PC12 cells or KCI from primary cerebellar granule neurons (CGCs). Sequestation of Fast by incubat ion with a Fas-Fc decoy inhibits apoptosis in all three cases. CGCs derived from gld mice (defective in Fast) are less sensitive to apoptosis caused b y KCl removal than wild-type neurons. In PC12 cells, protection Is also con ferred by a c-Jun mutant lacking JNK phosphoacceptor sites and a small mole cule inhibitor of p38 mitogen-activated protein kinase and JNK, which inhib its Fast induction. Hence, the JNK-to-c-Jun-to-FasL pathway is an important mediator of stress-induced neuronal apoptosis.