Nerve growth factor-induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor

Abstract

PC12 cells, which differentiate morphologically and biochemically into sympathetic neuronlike cells in response to nerve growth factor, also respond to epidermal growth factor . The response to epidermal growth factor is similar in certain respects to the response to nerve growth factor . Both peptides produce rapid increases in cellular adhesion and 2-deoxyglucose uptake and both induce ornithine decarboxylase . But nerve growth factor causes a decreased cell proliferation and a marked hypertrophy of the cells. In contrast, epidermal growth factor enhances cell proliferation and does not cause hypertrophy . Nerve growth factor induces the formation of neurites ; epidermal growth factor does not.When both factors are presented simultaneously, the cells form neurites . Furthermore, the biological response to epidermal growth factor, as exemplified by the induction of ornithine decarboxylase, is attenuated by prior treatment of the cells with nerve growth factor . PC12 cells have epidermal growth factor receptors. The binding of epidermal growth factor to these receptors is rapid and specific, and exhibits an equilibrium constant of 1 .9 x 10 -9 M. Approximately 80,000 receptors are present per cell, and this number is independent of cell density.Treatment of the cells with nerve growth factor reduces the amount of epidermal growth factor binding by at least 809'0. The decrease in receptor binding begins after -12-18 h of nerve growth factor treatment and is complete within 3 d . Scatchard plots indicate that the number of binding sites decreases, not the affinity of the binding sites for epidermal growth factor .The rat pheochromocytoma clone PC 12 has been used extensively as a model of neuronal differentiation . This clone, developed from an adrenal tumor by Greene and his colleagues (12, 18-20, 22, 45), is of adrenergic neural crest derivation . The cells grow readily under standard conditions and exhibit many of the properties of adrenal medullary chromaffin cells . In the presence of nerve growth factor in nanogram or even subnanogram amounts, the cells differentiate into a phenotype resembling sympathetic neurons . The changes occur within a few days and include process formation, electrical excitability, amine uptake and storage, and a cessation of cell division . The cells contain increased levels of certain transmitter-synthesizing enzymes (13,20,41) and will make synapses with appropriate target tissues (41). The differentiation appears to be reversible, but except for this, it resembles, as far as has been explored, the changes occurring in normal cells differentiating into sympathetic neurons .

The role of phosphatidic acid in platelet-derived growth factor-induced proliferation of rat hepatic stellate cells

“…42 For example, in PC12 cells, neuronal growth factor leads to sustained ERK activation and favors cell differentiation, whereas epidermal growth factor leads to a more transient activation of ERK and is mitogenic. [43][44][45] In these cells only the sustained activation of ERK is associated with nuclear translocation. 43 In contrast, and similar to our data, sustained ERK activation is associated with proliferation rather than differentiation in fibroblast cell lines.…”

Nerve growth factor and epidermal growth factor stimulate clusterin gene expression in PC12 cells

“…To study neuronal differentiation the cell line PC12 serves as a widely accepted model system (reviewed in [15,16]). PC12 cells can be induced to differentiate into a neuronal phenotype by nerve growth factor (NGF) [17] or to proliferate by epidermal growth factor (EGF) [18]. NGF and EGF signal transduction have several pathways in common [15,[19][20][21] and it has been a critical question for the understanding of neuronal differentiation to identify the pathway(s) distinguishing between proliferation and differentiation.…”

Long-term, heterologous down-regulation of the epidermal growth factor receptor in PC12 cells by nerve growth factor.

“…The PC12 cells, of course, carry NGF receptors (Herrup and Thoenen, 1979;Landreth and Shooter, 1980) and the binding of NGF to these specific receptors triggers many and diverse arrays of cellular responses, including both shortterm, rapid membranal changes, and long-term alterations in cell properties associated with changes in transcription (Guroff, 1983). Among these responses, NGF-induced differentiation in PC12 involves a transition from a mitotic to a nonmitotic state.In this regard, it was of interest to observe that the PCI2 ceils also have receptors for epidermal growth factor (EGF) (Huff and Guroff, 1979;Huff et al, 1981;Boonstra et al, 1985). This peptide is a potent mitogen for many of the cells I. Abbreviations used in this paper: EGF, epidermal growth factor; NGF, nerve growth factor.…”

“…In this regard, it was of interest to observe that the PCI2 ceils also have receptors for epidermal growth factor (EGF) (Huff and Guroff, 1979;Huff et al, 1981;Boonstra et al, 1985). This peptide is a potent mitogen for many of the cells I. Abbreviations used in this paper: EGF, epidermal growth factor; NGF, nerve growth factor.…”

“…with which it interacts, and is a mild mitogen for PC12 (Huff et al, 1981). Since the cells, then, have receptors for both a differentiating agent and a mitogen, experiments in this laboratory have been designed to explore what happens when the cells are treated with both agents.In previous studies it has been shown (Huff and Guroff, 1979;Huff et al, 1981) that treatment of the cells with NGF reduces the amount of EGF binding to the cells by 80 % or more. Scatchard plots have indicated that the number of EGF receptors decreases, but that the affinity of the remaining receptors for EGF remains constant.…”