Figure 7.

Model of sympathetic neuron apoptosis induced by NGF withdrawal or p75NTR activation. Both of these apoptotic stimuli increase p53 and Bax protein levels, and require elevated p53 levels to efficiently promote cell death. Neuronal death induced by activated MEKK1 also increases p53 and Bax protein levels, and requires elevated levels of p53 protein. NGF withdrawal-mediated sympathetic neuron death increases JNK and c-jun phosphorylation and activity, and requires c-jun (Estus et al., 1994; Ham et al., 1995). p75NTR activation in sympathetic neurons also leads to hyperphosphorylation of c-jun, presumably via JNK (Bamji et al., 1998). Bax is also essential for sympathetic neuron apoptosis in vivo and in vitro (Deckwerth et al., 1996; Easton et al., 1997). The precise MEKK or JNK family member in these pathways is not known, and other intermediate proteins, such as SEK1 (Sanchez et al., 1994) are likely involved as intermediate steps in this hypothetical cascade. Moreover, although this model shows JNK signaling to p53 via c-jun, recent work indicates that JNK can directly interact with and phosphorylate p53 (Hu et al., 1997). p53 may induce death by increasing Bax protein or activity, or via other p53 target proteins (Polyak et al., 1997).