The goal of this project is to investigate basic mechanisms through which polypeptide hormones, growth factors and neurotransmitters regulate gene expression in responsive target tissues. Over the past decade, our knowledge of steroid hormone action has become considerably clearer. Yet, information is still lacking on the mechanisms by which different agents that bind to cell-surface receptors affect gene expression. This project will undertake studies of cardiovascular receptor mechanism operative ar the genomic level. Since we are probing fundamental mechanisms in signal transduction we propose utilizing simple model systems. However, significant effort will be given to studying the regulation of the gene coding for atrial natriuretic factor (ANF) in cardiac myocytes. We have already identified several transcription factors that respond to CAMP and diacylglycerol, second messenger systems common to most cardiovascular receptors. These three transcription factors, activator proteins 1, 2 and 3 (AP-1, AP-2 and AP- 3), were recently shown in our laboratory to participate in signal transduction by the protein kinase A and protein kinase C systems. This project will focus on understanding the mechanisms f action of these factors. DNA probes, expression vectors, and specific antisera are available for all of them. Studies will be undertaken as to the role of these factors in regulated transcription of target genes in response to stimulation of cell surface receptors. Cellular protein kinases and other proteins that interact with these transcriptional activators will be identified and purified. Site-directed mutagenesis will be used to determine the functional organization of the activator molecules and the significance of the various interactions in which they participate. An important paradigm will be the regulation of ANF transcription by growth factors, angiotensin and hypertrophy. These studies should provide detailed information on the basic signal transduction pathways by hormones and neurotransmitters, such as angiotensin and norepinephrine.
Showing the most recent 10 out of 187 publications
