HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 28, 26111-26119, July 11, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/28/26111    most recent M212750200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Perrot, V. Articles by Rechler, M. M. Search for Related Content PubMed PubMed Citation Articles by Perrot, V. Articles by Rechler, M. M. Social Bookmarking                      What's this?

Characterization of Insulin Inhibition of Transactivation by a C-terminal Fragment of the Forkhead Transcription Factor Foxo1 in Rat Hepatoma Cells^*

Valérie Perrot  and Matthew M. Rechler

From the Growth and Development Section, Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

The transcription factor Foxo1 controls the expression of genes involved in fundamental cellular processes. In keeping with its important physiological roles, Foxo1 activity is negatively regulated in response to growth factors and cytokines that activate a phosphatidylinositol 3-kinase (PI 3-kinase) protein kinase B (PKB)/Akt pathway. PKB/Akt-mediated phosphorylation of Foxo1 has been shown to result in the inhibition of target gene transcription and to trigger the export of Foxo1 from the nucleus, which is generally believed to explain the subsequent decrease of transcription. In the present study, using a chimeric protein in which a C-terminal fragment of Foxo1 (amino acids 208–652) containing the transactivation domain is fused to the yeast Gal4 DNA binding domain, we present evidence showing that insulin can directly regulate transactivation by Foxo1 in H4IIE rat hepatoma cells. Insulin inhibition of Foxo1-(208–652)-stimulated transactivation is mediated by PI 3-kinase but in contrast to full-length Foxo1, does not require either of the two PKB/Akt phosphorylation sites (Ser²⁵³ and Ser³¹⁶) present in the protein fragment. Using mutational and deletion studies, we identify two potential phosphorylation sites, Ser³¹⁹ and Ser⁴⁹⁹, as well as a 15-amino acid region located between residues 350 and 364 that are critical for insulin inhibition of transactivation by Foxo1-(208–652). We conclude that the transcriptional activity of Foxo1 is regulated at different levels by insulin: transactivation, as well as DNA binding and nuclear exclusion. These different regulatory mechanisms allow the precise control of transcription of Foxo1 target genes by insulin.

Received for publication, December 13, 2002 , and in revised form, April 14, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bldg. 30, Rm. 207, 9000 Rockville Pike, Bethesda, MD 20892-4340. Tel.: 301-402-7529; Fax: 301-402-0823; E-mail: vperrot{at}nidcr.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. A Glauser and W. Schlegel The emerging role of FOXO transcription factors in pancreatic {beta} cells J. Endocrinol., May 1, 2007; 193(2): 195 - 207. [Abstract] [Full Text] [PDF]

				V. Perrot and M. M. Rechler The Coactivator p300 Directly Acetylates the Forkhead Transcription Factor Foxo1 and Stimulates Foxo1-Induced Transcription Mol. Endocrinol., September 1, 2005; 19(9): 2283 - 2298. [Abstract] [Full Text] [PDF]

				K. Yamagata, H. Daitoku, Y. Shimamoto, H. Matsuzaki, K. Hirota, J. Ishida, and A. Fukamizu Bile Acids Regulate Gluconeogenic Gene Expression via Small Heterodimer Partner-mediated Repression of Hepatocyte Nuclear Factor 4 and Foxo1 J. Biol. Chem., May 28, 2004; 279(22): 23158 - 23165. [Abstract] [Full Text] [PDF]

				W.-C. Tsai, N. Bhattacharyya, L.-Y. Han, J. A. Hanover, and M. M. Rechler Insulin Inhibition of Transcription Stimulated by the Forkhead Protein Foxo1 Is Not Solely due to Nuclear Exclusion Endocrinology, December 1, 2003; 144(12): 5615 - 5622. [Abstract] [Full Text] [PDF]

				P. Dowell, T. C. Otto, S. Adi, and M. D. Lane Convergence of Peroxisome Proliferator-activated Receptor {gamma} and Foxo1 Signaling Pathways J. Biol. Chem., November 14, 2003; 278(46): 45485 - 45491. [Abstract] [Full Text] [PDF]