Tc. Harding et al., Inhibition of JNK by overexpression of the JNK binding domain of JIP-1 prevents apoptosis in sympathetic neurons, J BIOL CHEM, 276(7), 2001, pp. 4531-4534
Studies in non-neuronal cells show that c-Jun N-terminal kinases (JNK) play
a key role in apoptotic cell death. In some neurons JNK is also thought to
initiate cell death by the activation of c-Jun, JNK inhibition has been ac
hieved pharmacologically by inhibiting upstream kinases, but there has been
no direct demonstration that inhibition of JNK can prevent neuronal death.
We have therefore examined whether the JNK binding domain (JBD) of JNK-int
eracting protein-1 (JIP-1, a scaffold protein and specific inhibitor of JNK
) can inhibit c-Jun phosphorylation and support the survival of sympathetic
neurons deprived of NGF. We show that expression of the JBD in >80% of neu
rons was sufficient to prevent the phosphorylation of c-Jun and its nuclear
accumulation as well as abrogate neuronal cell death induced by NGF depriv
ation. JBD expression also preserved the capacity of mitochondria to reduce
MTT. Interestingly, although the PTB domain of JIP was reported to interac
t with rhoGEF, expression of the JBD domain was sufficient to localize the
protein to the membrane cortex and growth cones. Hence, JNK activation is a
key event in apoptotic death induced by NGF withdrawal, where its point of
action lies upstream of mitochondrial dysfunction.