This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Onuma, H. Articles by O’Brien, R. M. Search for Related Content PubMed PubMed Citation Articles by Onuma, H. Articles by O’Brien, R. M.

Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) Binding and the Inhibition of Basal Glucose-6-Phosphatase Catalytic Subunit Gene Transcription by Insulin

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Richard M. O’Brien, Department of Molecular Physiology and Biophysics, 761 Preston Research Building, Vanderbilt University Medical School, Nashville, Tennessee 37232-0615.

Insulin inhibits transcription of the genes encoding the glucose-6-phosphatase catalytic subunit (G6Pase), phosphoenolpyruvate carboxykinase, and IGF binding protein-1 through insulin response sequences (IRSs) that share the same core sequence, T(G/A)TTTT(G/T). The transcription factors FOXO1a and FOXO3a have been shown to bind these elements, but there are conflicting reports as to whether this binding correlates with the action of insulin on gene transcription. Some researchers concluded, from overexpression experiments using FOXO1a, that binding correlated with the insulin response, whereas others concluded, mainly from gel retardation competition experiments using FOXO3a, that it did not. We show here that, although these factors can differentially activate gene transcription in a context-dependent manner, these conflicting data are not explained by a difference in FOXO1a and FOXO3a binding specificity. Instead, we find that gel retardation competition and binding experiments give different results; the latter reveal a correlation between FOXO1a/3a binding and the inhibition of basal G6Pase gene transcription by insulin. In addition, these data show that the binding of FOXO1a/3a to two adjacent IRSs in the G6Pase promoter is cooperative and that promoter context alters the specific IRS base requirements for FOXO1a-stimulated fusion gene expression. Surprisingly, an analysis of insulin action mediated through the G6Pase and IGF binding protein-1 IRSs in the context of a heterologous thymidine kinase promoter reveals that signaling through the latter does not support the accepted model for insulin-stimulated FOXO nuclear exclusion.

This article has been cited by other articles:

				J.-Y. Yang and M.-C. Hung A New Fork for Clinical Application: Targeting Forkhead Transcription Factors in Cancer Clin. Cancer Res., February 1, 2009; 15(3): 752 - 757. [Abstract] [Full Text] [PDF]

				D. S. Waddell, L. M. Baehr, J. van den Brandt, S. A. Johnsen, H. M. Reichardt, J. D. Furlow, and S. C. Bodine The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E785 - E797. [Abstract] [Full Text] [PDF]

				J. Nakae, Y. Cao, M. Oki, Y. Orba, H. Sawa, H. Kiyonari, K. Iskandar, K. Suga, M. Lombes, and Y. Hayashi Forkhead Transcription Factor FoxO1 in Adipose Tissue Regulates Energy Storage and Expenditure Diabetes, March 1, 2008; 57(3): 563 - 576. [Abstract] [Full Text] [PDF]

				J. Halperin, S. Y. Devi, S. Elizur, C. Stocco, A. Shehu, D. Rebourcet, T. G. Unterman, N. D. Leslie, J. Le, N. Binart, et al. Prolactin Signaling through the Short Form of Its Receptor Represses Forkhead Transcription Factor FOXO3 and Its Target Gene Galt Causing a Severe Ovarian Defect Mol. Endocrinol., February 1, 2008; 22(2): 513 - 522. [Abstract] [Full Text] [PDF]

				P. O. Wiebe, J. D. Kormish, V. T. Roper, Y. Fujitani, N. I. Alston, K. S. Zaret, C. V. E. Wright, R. W. Stein, and M. Gannon Ptf1a Binds to and Activates Area III, a Highly Conserved Region of the Pdx1 Promoter That Mediates Early Pancreas-Wide Pdx1 Expression Mol. Cell. Biol., June 1, 2007; 27(11): 4093 - 4104. [Abstract] [Full Text] [PDF]

				L. Qiao and J. Shao SIRT1 Regulates Adiponectin Gene Expression through Foxo1-C/Enhancer-binding Protein {alpha} Transcriptional Complex J. Biol. Chem., December 29, 2006; 281(52): 39915 - 39924. [Abstract] [Full Text] [PDF]