Coordinate regulation of the inducible forms of prostaglandin synthase and nitric oxide synthase in fibroblasts and macrophages.

Abstract

For many years our laboratory has been interested in i) identifying the “primary response” genes (1) whose message levels are stimulated in response to extracellular ligands such as growth factors, hormones, and neurotransmitters, and ii) characterizing both the regulation of the transcription of these genes in response to ligand-induced signal transduction pathways and the role of the products of these genes in the ligand-induced cellular responses. We cloned cDNAs for seven genes induced in response to mitogenic stimulation of Swiss 3T3 cells by tetradecanoyl phorbol acetate (TPA). We refer to these genes as TPA Induced Sequences, or TIS genes (2). cDNAs for many of these same genes have been cloned as serum-induced genes from fibroblasts, nerve growth factor-induced genes from neuronal cell lines, and mitogen-stimulated genes induced after lymphokine stimulation of lymphocytes (3). Many of these genes encode inducible transcription factors such as c-fos, cjun, egr-1/TlS8, and N10/nur77/TISl (3). These inducible transcription factors are required to transcribe the secondary response genes whose products participate in the cascade of gene expression leading to ligand-induced phenotypic changes, such as entry into the cell cycle or ligand-induced differentiation. Other ligand-inducible primary response genes, such as the JC and KE genes, encode secreted, cytokine-like molecules (3). It seems likely that the role of these gene products is to signal neighboring cells that the responding cell is undergoing a profound, ligand-induced change in cell physiology.