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  • Original Paper
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Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells

Oncogene volume 18, pages 2055–2068 (1999)Cite this article

Abstract

Nerve growth factor induces differentiation and survival of rat PC12 pheochromocytoma cells. The activation of the erk cascade has been implicated in transducing the multitude of signals induced by NGF. In order to explore the role of this signaling cascade in NGF mediated survival, differentiation and proliferation, we generated recombinant adenoviruses which express the intermediates of the erk cascade in their wild type, dominant negative and constitutively activated forms. We show that differentiation of PC12 cells requires activity of the ras/erk pathway, whereas inhibition of this pathway had no effect on survival or proliferation. Constitutively active forms of ras, raf and mek induced PC12 cell differentiation, while dominant interfering forms inhibited differentiation. Survival of PC12 cells in serum-free medium did not require activity of the ras/erk pathway. Instead, PI3 Kinase signaling was necessary for PC12 cell survival. Interestingly, constitutively activated versions of raf and mek were able to promote survival, but again this was dependent on activation of PI3 Kinase. Therefore, at least two distinct signaling pathways are required in PC12 cells for mediation of NGF functions.

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Acknowledgements

We wish to thank L Feig for providing the DN ras and wt ras DNA; M White for the CA ras DNA; U Raff for the raf DNA constructs; and M Cobb and J Frost for the Erk constructs. Thanks to B Gerard for the pAC-CMV vector and C Newgard for the pJM17 vector for adenovirus generation. We would also like to thank J Alcorn for the B-galactosidase expressing adenovirus and for advice in recombinant adenovirus generation. This work was supported by NINDS ROI NS 34296. LFP and LJK were partially supported by DOD grant DAMD17-97-1-7343, LKJ was supported by NIH T326M08203.

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  1. Center for Developmental Biology, University of Texas, Southwestern Medical Center, Dallas, 75235-9133, Texas, USA

    L J Klesse, K A Meyers & L F Parada

  2. Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK

    C J Marshall

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  1. L J Klesse
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Klesse, L., Meyers, K., Marshall, C. et al. Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells. Oncogene 18, 2055–2068 (1999). https://doi.org/10.1038/sj.onc.1202524

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