DESCRIPTION (from Abstract): Nerve growth factor (NGF) is a protein required for the development and maintenance of the nervous system. The actions of NGF are mediated by two receptors, gp75 and the tyrosine kinase TrkA, which synergize with each other to activate multiple signal transduction pathways. The focus of this proposal is a novel pathway that regulates expression of p21WAFl, an inhibitor of cyclin-dependent kinases and, thereby, influences whether cells proliferate, differentiate, or undergo apoptosis. We are emphasizing p21WAF1 because it is up-regulated early in differentiation of the neuroblastoma line SH-SY5Y cells and because suppression of p21WAF1 with antisense oligonucleotides results in apoptosis. Up-regulation of p21WAF1 expression also occurs during differentiation of PC12 cells. Nitric oxide synthases (NOS), nitric oxide (NO) and the tumor suppressor p5 may be intermediates in this pathway. Each Specific Aim of this proposal deals with a different segment of the pathway. In the first specific aim, we will determine which NGF receptor activates the NO pathway. For Specific Aim 2, we will determine which NGF activated signal transduction molecules regulate NOS expression. In Specific Aim , we will elucidate the mechanism by which NO activates the p5-p21WAF1 link in this pathway. For Specific Aim 4, we will analyze the biological and biochemical consequences of NGF induction of NOS. In Specific Aim 5, we ask whether NO is an intercellular messenger regulating cell proliferating during differentiation. The mechanism by which neurotrophic factors control cell proliferation is directly relevant to neuronal development, neural regeneration, neurodegenerative diseases, and neural tumors.