Ngf

Regulation of growth and differentiation Regulation of survival

The importance of p53 and p73 has also been emphasized by the important observation that, in cultured neuroblastoma and other cancer cells, p73 directly transactivates the ANp73 gene by binding to its promoter after treating the cells with genotoxic reagents, e.g., cisplatin (Nakagawa et al. 2002). The induced ANp73 protein in turn interacts with either wild-type p53 or TAp73 and inhibits their proapop-totic function; thus, ANp73 can act as an oncogene and as an inhibitor of wild-type p53 and TAp73. The presence of this autoinhibitory feedback loop among p53, TAp73, and ANp73 may at least in part explain why there is no mutation of the p73 gene in cancers.

p53 is associated with TrkA via the proto-oncogene product c-Abl as an adaptor or bridging molecule, suggesting that it may also play a role in Trk signaling (Yano et al. 2000) (Fig. 5.7). The activation of Ras by NGF stimulation of the TrkA receptor induces p53 nuclear translocation and growth arrest in PC 12 cells (Hughes et al. 2000). The c-Ha-Ras gene could be a target of p53, and protein products induce a positive feedback loop by activating p14ARF which counteracts the negative feedback loop mediated by mdm2 (Deguin-Chambon et al. 2000). These observations strongly suggest that p53 and p73 tumor suppressors function in neurotrophin signaling and modulate the growth, differentiation, and apoptosis of neurons.

In neuroblastoma and some other human cancers, wild type p53 is often localized in the cytoplasm (Moll et al. 1995). Although the regulatory mechanism of cellular localization of p53 and p73 is still unknown, activated Ras in NGF/TrkA signaling stimulates the nuclear translocation of p53 and leads to growth arrest by the induction of p21WAF1 in PC 12 cells (Hughes et al. 2000). Furthermore, some fractions of recurrent neuroblastomas and neuroblas-toma cell lines acquire mutation of the p53 gene (Tweddle et al. 2001).

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