A Cell Genetic Study on the Molecular Mechanism of Hormone Receptor Systems

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Epidermal growth factor (EGF) and insulin interact with their own membrane receptors and regulate cellular metabolism and growth through generating mitogenic and hormonal signals. In order to facilitate the studies on the mechanisms of signal transduction, we have taken a cell genetic approach and devised selection procedures by which to isolate cell variants that are defective or extraordinary in their response. These include the use of toxic hybrid hormones, immunotoxin and mitotic shake-off techniques. Several series of genetic variants have been isolated. The characteristics of the insulin-diphtheria toxin A fragment-resistant variants provided genetic evidence for the divergence of the insulin receptor-mediated mitogenic and hormonal signals during the post-receptor pathways which is apparently regulated by the insulin-dependent phosphorylation. Also, the analysis of dihydroteleocidin B-nonresponsive variants suggested that phosphatidylinositol turnover followed by protein kinase C activation is not sufficient for mitogenic stimulation and that the coordination of the protein kinase C system with the growth factor receptor system may be necessary for full mitogenic response. Chromosomal mapping of human genes related to EGF receptor and multi-drug resistance has also been carried out.