GSBS Student Publications

Title

A novel, nerve growth factor-activated pathway involving nitric oxide, p53, and p21WAF1 regulates neuronal differentiation of PC12 cells

UMMS Affiliation

Graduate School of Biomedical Sciences; Graduate School of Biomedical Sciences; Worcester Foundation for Biomedical Research; Department of Biochemistry and Molecular Pharmacology

Date

9-20-1997

Document Type

Article

Medical Subject Headings

Animals; Cell Differentiation; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Nerve Growth Factors; Neurons; Nitric Oxide; PC12 Cells; Promoter Regions (Genetics); Rats; Signal Transduction; Tumor Suppressor Protein p53

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

During development, neuronal differentiation is closely coupled with cessation of proliferation. We use nerve growth factor (NGF)-induced differentiation of PC12 pheochromocytoma cells as a model and find a novel signal transduction pathway that blocks cell proliferation. Treatment of PC12 cells with NGF leads to induction of nitric oxide synthase (NOS) (Peunova, N., and Enikolopov, G. (1995) Nature 375, 68-73). The resulting nitric oxide (NO) acts as a second messenger, activating the p21(WAF1) promoter and inducing expression of p21(WAF1) cyclin-dependent kinase inhibitor. NO activates the p21(WAF1) promoter by p53-dependent and p53-independent mechanisms. Blocking production of NO with an inhibitor of NOS reduces accumulation of p53, activation of the p21(WAF1) promoter, expression of neuronal markers, and neurite extension. To determine whether p21(WAF1) is required for neurite extension, we prepared a PC12 line with an inducible p21(WAF1) expression vector. Blocking NOS with an inhibitor decreases neurite extension, but induction of p21(WAF1) with isopropyl-1-thio-beta-D-galactopyranoside restored this response. Levels of p21(WAF1) induced by isopropyl-1-thio-beta-D-galactopyranoside were similar to those induced by NGF. Therefore, we have identified a signal transduction pathway that is activated by NGF; proceeds through NOS, p53, and p21(WAF1) to block cell proliferation; and is required for neuronal differentiation by PC12 cells.

Rights and Permissions

Citation: J Biol Chem. 1997 Sep 19;272(38):24002-7.

Related Resources

Link to article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

9295352