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Department of Pediatrics (S.K.D., A.S., A.O.S., D.R.P.), Baylor College of Medicine, Houston, Texas 77030; Department of Medicine (D.Y., J.G.J.), University of Texas Health Science Center, San Antonio, Texas 78284; and Department of Pathology and Laboratory Medicine (F.G.B.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: David R. Powell, Texas Children’s Hospital, Feigin Center, MC 3–2482, 6621 Fannin, Houston, Texas 77030. E-mail: dpowell{at}bcm.tmc.edu
The insulin response element (IRE) in the IGFBP-1 promoter, and in other gene promoters, contains a T(A/G)TTT motif essential for insulin inhibition of transcription. Studies presented here test whether FKHR may be the transcription factor that confers insulin inhibition through this IRE motif. Immunoblots using antiserum to the synthetic peptide FKHR413–430, RNase protection, and Northerns blots show that FKHR is expressed in HEP G2 human hepatoma cells. Southwestern blots, electromobility shift assays, and DNase I protection assays show that Escherichia coli-expressed GST-FKHR binds specifically to IREs from the IGFBP-1, PEPCK and TAT genes; however, unlike HNF3ß, another protein proposed to be the insulin regulated factor, GST-FKHR does not bind the insulin unresponsive G/C-A/C mutation of the IGFBP-1 IRE. When HEP G2 cells were cotransfected with FKHR expression vectors and with IGFBP-1 promoter plasmids containing either native or mutant IREs, FKHR expression induced a 5-fold increase in activity of the native IGFBP-1 promoter but no increase in activity of promoter constructs containing insulin unresponsive IRE mutants. These data suggest that FKHR, and/or a related family member, is the important T(G/A)TTT binding protein that confers the inhibitory effect of insulin on gene transcription.
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D. Schmoll, K. S. Walker, D. R. Alessi, R. Grempler, A. Burchell, S. Guo, R. Walther, and T. G. Unterman Regulation of Glucose-6-phosphatase Gene Expression by Protein Kinase Balpha and the Forkhead Transcription Factor FKHR. EVIDENCE FOR INSULIN RESPONSE UNIT-DEPENDENT AND -INDEPENDENT EFFECTS OF INSULIN ON PROMOTER ACTIVITY J. Biol. Chem., November 10, 2000; 275(46): 36324 - 36333. [Abstract] [Full Text] [PDF]
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M. Waltner-Law, M. C. Daniels, C. Sutherland, and D. K. Granner NF-kappa B Inhibits Glucocorticoid and cAMP-mediated Expression of the Phosphoenolpyruvate Carboxykinase Gene J. Biol. Chem., October 6, 2000; 275(41): 31847 - 31856. [Abstract] [Full Text] [PDF]
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R. K. Hall, T. Yamasaki, T. Kucera, M. Waltner-Law, R. O'Brien, and D. K. Granner Regulation of Phosphoenolpyruvate Carboxykinase and Insulin-like Growth Factor-binding Protein-1 Gene Expression by Insulin. THE ROLE OF WINGED HELIX/FORKHEAD PROTEINS J. Biol. Chem., September 22, 2000; 275(39): 30169 - 30175. [Abstract] [Full Text] [PDF]
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C. M. Cahill, G. Tzivion, N. Nasrin, S. Ogg, J. Dore, G. Ruvkun, and M. Alexander-Bridges Phosphatidylinositol 3-Kinase Signaling Inhibits DAF-16 DNA Binding and Function via 14-3-3-dependent and 14-3-3-independent Pathways J. Biol. Chem., April 13, 2001; 276(16): 13402 - 13410. [Abstract] [Full Text] [PDF]
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D. Yeagley, S. Guo, T. Unterman, and P. G. Quinn Gene- and Activation-specific Mechanisms for Insulin Inhibition of Basal and Glucocorticoid-induced Insulin-like Growth Factor Binding Protein-1 and Phosphoenolpyruvate Carboxykinase Transcription. ROLES OF FORKHEAD AND INSULIN RESPONSE SEQUENCES J. Biol. Chem., August 31, 2001; 276(36): 33705 - 33710. [Abstract] [Full Text] [PDF]
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E. R. Schuur, A. V. Loktev, M. Sharma, Z. Sun, R. A. Roth, and R. J. Weigel Ligand-dependent Interaction of Estrogen Receptor-alpha with Members of the Forkhead Transcription Factor Family J. Biol. Chem., August 31, 2001; 276(36): 33554 - 33560. [Abstract] [Full Text] [PDF]
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K. Kishida, I. Shimomura, H. Kondo, H. Kuriyama, Y. Makino, H. Nishizawa, N. Maeda, M. Matsuda, N. Ouchi, S. Kihara, et al. Genomic Structure and Insulin-mediated Repression of the Aquaporin Adipose (AQPap), Adipose-specific Glycerol Channel J. Biol. Chem., September 21, 2001; 276(39): 36251 - 36260. [Abstract] [Full Text] [PDF]
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 N. Nasrin, S. Ogg, C. M. Cahill, W. Biggs, S. Nui, J. Dore, D. Calvo, Y. Shi, G. Ruvkun, and M. C. Alexander-Bridges DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells PNAS, September 12, 2000; 97(19): 10412 - 10417. [Abstract] [Full Text] [PDF]
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