The goal of this project is to understand the mechanisms of signal transduction in response to a variety of cytokines and growth factors. When a ligand binds to its receptor, a signaling cascade is initiated which involves the phosphorylation of the receptor and/or other cytoplasmic proteins. These proteins, which include specific protein kinases and phosphatases, then phosphorylate DNA binding proteins (transcription factors) which are ultimately responsible for the regulation of expression of cytokine and growth factor responsive genes. We are currently studying a collection of murine cell lines which carry either the native or mutated cytoplasmic regions of the growth hormone receptor. By examining the activation and deactivation of a specific transcription complex, we are able to identify regions of the receptor that are required for signaling in response to the growth factor. We can also delineate regions of the receptor that associate with other components of this signaling cascade. This information furthers our understanding of the action of growth hormone on its receptor. This research program is increasing our understanding of receptor function and how cytokines or growth factors are able to interact to regulate cell expression. It now appears that many of the receptors and other signaling components are related and in fact used by more than one cytokine. Since cytokines comprise an important group of biological products which are reviewed by CBER, this research is relevant for my review responsibilities. These studies help us understand manufacturing issues for recombinant cytokines and will increase our understanding of the clinical efficacy and toxicities associated with the clinical use of interferons and cytokines. This knowledge will allow us to make better decisions regarding the regulation of cytokine therapies.
