Possible Antiapoptotic Role for Nuclear PI(3,4,5)P 3

Abstract

Nerve growth factor (NGF) is required for survival of some neurons. Ahn et al. examined potential signaling mechanisms that might mediate the antiapoptotic effects of NGF. In particular, they focused on a role for phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], well known as a cytoplasmic second messenger but also likely to function in the nucleus. Previous work from the authors had shown that in an in vitro model recapitulating the nuclear DNA fragmentation associated with apoptosis, PI(3,4,5)P 3 mimicked the effect of NGF to inhibit DNA fragmentation. Therefore, they searched for proteins from nuclear extracts of NGF-treated cells that would interact specifically with PI(3,4,5)P 3 conjugated to beads. One candidate interacting protein was B23 (also called NPM or nucleophosmin), a nuclear phosphoprotein that has been implicated in numerous regulatory functions, including inhibition of apoptosis. Immunodepletion of B23 decreased the protective effect of NGF in the in vitro assay system, and depletion of B23 after treatment of PC12 cells with short-hairpin RNA increased DNA fragmentation after an apoptotic stimulus, an effect not reversed by treatment of cells with NGF. In the in vitro assay, addition of PI(3,4,5)P 3 enhanced the inhibitory effect of B23 on DNA fragmentation. In stably transfected PC12 cells, expression of a mutant form of B23 that no longer bound PI(3,4,5)P 3 was less effective than the wild-type protein in protecting against DNA damage. At least in stably transfected cells, B23 appeared to associate with caspase-activated DNAse (CAD), the enzyme that mediates DNA fragmentation in apoptosis. The authors proposed that some of the protective effects of NGF against apoptosis may occur through a mechanism where NGF-stimulated formation of PI(3,4,5)P 3 may enhance inhibition of CAD by B23. J.-Y. Ahn, X. Liu, D. Cheng, J. Peng, P.-K. Chan, P. A. Wade, K. Ye, Nucleophosmin/B23, a nuclear PI(3,4,5)P 3 receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD. Mol. Cell 18 , 435-445 (2005). [PubMed]