NRIF is an essential component of apoptotic signaling by the p75 neurotrophin receptor

Abstract

Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. I report that the Neurotrophin Receptor Interacting Factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon NGF withdrawal, nrif -/- sympathetic neurons underwent apoptosis, while p75 mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif -/- neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. While I have shown NRIF to be essential for p75-induced cell death, there is still relatively little known about this protein. To this end, I demonstrate that NRIF is capable of inducing apoptosis in primary cells in the absence of p75 activation. This apoptotic program involves the activation of caspase 3 and the release of cytochrome c from the mitochondria. NRIF expression in primary cells is not sufficient to activate JNK but NRIF-activated cell death requires both p53 and its upstream activator p19Arf. NRIF is found in the nucleus after receptor activation, suggesting that this molecule may act as a transcription regulator. Consistent with this hypothesis, NRIF requires its putative DNA binding domain to maximally induce apoptosis. Finally, I examined the role of NRIF as a tumor suppressor and find that while this protein causes cell cycle arrest and apoptosis, the absence of nrif in vivo does not predispose mice to spontaneous tumor development. Taken together, these results establish NRIF as a proapoptotic protein that is essential for p75-mediated apoptosis.