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Paradoxical Regulation of Sp1 Transcription Factor by Glucagon

Veterans Affairs Medical Center, Research Services (C.N.K., R.P.C., G.M., S.S.S., A.M.-.H. and R.S.R.), and Departments of Medicine (S.S.S.), Pharmacology (S.S.S., R.S.R.), and Pathology (A.M.-H.), University of Tennessee Health Science Center, Memphis, Tennessee 38104

Address all correspondence and requests for reprints to: Solomon S. Solomon, M.D., Veterans Affairs Medical Center, Research Service (151), 1030 Jefferson Avenue, Memphis, Tennessee 38104. E-mail: . ssolomon{at}utmem.edu

Insulin is a potent regulator of Sp1 transcription factor. To examine if glucagon, which usually antagonizes insulin, regulates Sp1, we assessed the levels of Sp1 by Western blotting from H-411E cells exposed to glucagon with or without insulin. Glucagon alone (1.5 x 10^-9 to 1.5 x 10^-5 M) stimulated Sp1 accumulation but inhibited insulin’s (10,000 µU/ml) stimulatory effect on Sp1. We also assessed the effect of TNF-, wortmannin, a PI3K inhibitor, and cAMP-dependent protein kinase inhibitor on Sp1 accumulation. While TNF- (5 ng/ml) blocked insulin-stimulated Sp1, it failed to block stimulation of Sp1 by glucagon (1.5 x 10^-5 M). Similarly, wortmannin inhibited insulin- but not glucagon-stimulated Sp1, whereas protein kinase inhibitor had an opposite effect. Thus, insulin acts primarily via PI3K, and glucagon apparently stimulates through a cAMP-dependent pathway. Insulin increased the staining intensity of Sp1 seen exclusively in the nuclei of H-411E cells. Sp1 was demonstrable in both nucleus and cytoplasm after glucagon treatment. Finally, as judged by immunoblotting to specific antibody, insulin but not glucagon, stimulated O-glycosylation of Sp1. Thus, unique signaling mechanisms mediate the response of Sp1 to glucagon in the presence or absence of insulin.

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