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

Abstract

Nerve growth factor induces dierentiation 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, dierentiation 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 dierentiation of PC12 cells requires activity of the ras/erk pathway, whereas inhibition of this pathway had no eect on survival or proliferation. Constitutively active forms of ras, raf and mek induced PC12 cell dierentiation, while dominant interfering forms inhibited dierentiation. 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.

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

“…The Ras-ERK pathway differentially regulates differentiation and proliferation of cells according to the intensity and duration of the signal [36][37][38][39][40][41][42]. The importance of the kinetics of ERK activation in the determination of neuronal cell fate is dependent on the physiological status of Ras-ERK pathway activation [43][44][45]. Currently, it is not understood how cellular functions, such as differentiation and proliferation, are differently regulated via the common Ras-ERK pathway in response to intrinsic and extrinsic signals.…”

Early Single Cell Bifurcation of Pro- and Antiapoptotic States during Oxidative Stress

“…These genes are known to be transcriptionally activated by increased cellular oxidation (16,43,44) and by nerve growth factor (46,60). Evidence for an antiapoptotic role for ERK has been reported in PC-12 cells after growth factor withdrawal (13,59) and exposure to oxidative stress (16). ERK has also been reported to function as a suppressor of ROS in superior cervical ganglion neurons (61).…”

“…In PC-12 cells, ERK is mainly activated by growth factors and has been shown to be associated with cell proliferation, differentiation, and promotion of cell survival (13,16,58,59). H 2 O 2 increased the mRNA expression of the ERKdependent genes egr1, c-jun, c-fos, and mkp1.…”

HIV-Tat promotes cellular proliferation and inhibits NGF-induced differentiation through mechanisms involving Id1 regulation

“…NGF binds to and activates the TrkA receptor, which in turn phosphorylates and activates several substrates including Shc, PLC-g, and PI3-kinase, which consequently activate MAPK/ERK, PKC, and Akt (Klesse et al, 1999), respectively. The activation of the NGF/TrkA pathway also leads to the transient and tightly regulated expression of early response genes, such as inhibitor of differentiation (Id) proteins, which are necessary for the appropriate development and differentiation of the neuronal phenotype (Nagata and Todokoro, 1994;Einarson and Chao, 1995).…”

“…The rat pheochromocytoma cell line PC12 is a wellestablished model for studying the NGF network of signal transduction pathways in neuronal cells (Klesse et al, 1999). NGF binds to and activates the TrkA receptor, which in turn phosphorylates and activates several substrates including Shc, PLC-g, and PI3-kinase, which consequently activate MAPK/ERK, PKC, and Akt (Klesse et al, 1999), respectively.…”