Asavari Wagle

Date of Award

12-1997

Degree Name

Master of Arts

Department

Chemistry

First Advisor

Dr. Susan R. Stapleton

Second Advisor

Dr. David S. Reinhold

Third Advisor

Dr. Michael P. Dziewatkowski

Access Setting

Masters Thesis-Open Access

Abstract

Insulin, an anabolic hormone, exquisitely controls cellular physiology and metabolism by modulating the activity of key proteins which regulate metabolic and mitogenic events. Insulin activates several cytosolic proteins via a phosphorylation cascade, but only some of these proteins are required for its specific action. We have elucidated the insulin signal transduction cascade in primary rat hepatocytes, and outlined some of the events that are required for the insulin induced stimulation of glucose-6-phosphate dehydrogenase (G6PDH) gene expression. Using well-characterized and structurally different inhibitors, we show that insulin stimulation of the gene requires the IRS-1/P13K pathway and not the RAS/RAF/MAPK pathway. Gene expression is dependent on S6Kinase, which is controlled by P13K and as our results suggest, by Akt. Since previous studies have shown that the insulin mimetics, selenate and vanadate, control G6PDH gene expression, we studied the effect of these mimetics on the signaling proteins. Our results are consistent with the properties of vanadate as a phosphatase inhibitor. On the other hand, selenium signal transduction appears to be sequential and similar to insulin in the regulation of some of the proteins in the cascade.

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