This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rausa, F. M.
Right arrow Articles by Costa, R. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rausa, F. M.
Right arrow Articles by Costa, R. H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2003, p. 437-449, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.437-449.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Association between Hepatocyte Nuclear Factor 6 (HNF-6) and FoxA2 DNA Binding Domains Stimulates FoxA2 Transcriptional Activity but Inhibits HNF-6 DNA Binding

Francisco M. Rausa, Yongjun Tan, and Robert H. Costa*

Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607

Received 30 May 2002/ Returned for modification 6 August 2002/ Accepted 18 October 2002

In previous studies we used transgenic mice or recombinant adenovirus infection to increase hepatic expression of forkhead box A2 (FoxA2, previously called hepatocyte nuclear factor 3ß [HNF-3ß]), which caused diminished hepatocyte glycogen levels and reduced expression of glucose homeostasis genes. Because this diminished expression of FoxA2 target genes was associated with reduced levels of the Cut-Homeodomain HNF-6 transcription factor, we conducted the present study to determine whether there is a functional interaction between HNF-6 and FoxA2. Human hepatoma (HepG2) cotransfection assays demonstrated that HNF-6 synergistically stimulated FoxA2 but not FoxA1 or FoxA3 transcriptional activity, and protein-binding assays showed that this protein interaction required the HNF-6 Cut-Homeodomain and FoxA2 winged-helix DNA binding domains. Furthermore, we show that the HNF-6 Cut-Homeodomain sequences were sufficient to synergistically stimulate FoxA2 transcriptional activation by recruiting the p300/CBP coactivator proteins. This was supported by the fact that FoxA2 transcriptional synergy with HNF-6 was dependent on retention of the HNF-6 Cut domain LXXLL sequence, which mediated recruitment of the p300/CBP proteins. Moreover, cotransfection and DNA binding assays demonstrated that increased FoxA2 levels caused a decrease in HNF-6 transcriptional activation of the glucose transporter 2 (Glut-2) promoter by interfering with the binding of HNF-6 to its target DNA sequence. These data suggest that at a FoxA-specific site, HNF-6 serves as a coactivator protein to enhance FoxA2 transcription, whereas at an HNF-6-specific site, FoxA2 represses HNF-6 transcription by inhibiting HNF-6 DNA binding activity. This is the first reported example of a liver-enriched transcription factor (HNF-6) functioning as a coactivator protein to potentiate the transcriptional activity of another liver factor, FoxA2.


* Corresponding author. Mailing address: Department of Molecular Genetics (M/C 669), University of Illinois at Chicago College of Medicine, 900 S. Ashland Ave, Rm. 2220 MBRB, Chicago, IL 60607-7170. Phone: (312) 996-0474. Fax: (312) 355-4010. E-mail: RobCosta{at}uic.edu.


Molecular and Cellular Biology, January 2003, p. 437-449, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.437-449.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:

  • Hashita, T., Sakuma, T., Akada, M., Nakajima, A., Yamahara, H., Ito, S., Takesako, H., Nemoto, N. (2008). Forkhead Box A2-Mediated Regulation of Female-Predominant Expression of the Mouse Cyp2b9 Gene. Drug Metab. Dispos. 36: 1080-1087 [Abstract] [Full Text]  
  • Gladden, J. M., Meyer, B. J. (2007). A ONECUT Homeodomain Protein Communicates X Chromosome Dose to Specify Caenorhabditis elegans Sexual Fate by Repressing a Sex Switch Gene. Genetics 177: 1621-1637 [Abstract] [Full Text]  
  • Zhao, H., Friedman, R. D., Fournier, R. E. K. (2007). The Locus Control Region Activates Serpin Gene Expression through Recruitment of Liver-Specific Transcription Factors and RNA Polymerase II. Mol. Cell. Biol. 27: 5286-5295 [Abstract] [Full Text]  
  • Lehner, F., Kulik, U., Klempnauer, J., Borlak, J. (2007). The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 21: 1445-1462 [Abstract] [Full Text]  
  • Malin, D., Kim, I.-M., Boetticher, E., Kalin, T. V., Ramakrishna, S., Meliton, L., Ustiyan, V., Zhu, X., Kalinichenko, V. V. (2007). Forkhead Box F1 Is Essential for Migration of Mesenchymal Cells and Directly Induces Integrin-Beta3 Expression. Mol. Cell. Biol. 27: 2486-2498 [Abstract] [Full Text]  
  • Nakamura, K., Moore, R., Negishi, M., Sueyoshi, T. (2007). Nuclear Pregnane X Receptor Cross-talk with FoxA2 to Mediate Drug-induced Regulation of Lipid Metabolism in Fasting Mouse Liver. J. Biol. Chem. 282: 9768-9776 [Abstract] [Full Text]  
  • Beaudry, J.-B., Pierreux, C. E., Hayhurst, G. P., Plumb-Rudewiez, N., Weiss, M. C., Rousseau, G. G., Lemaigre, F. P. (2006). Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1{alpha} Are Required for Time-Specific Gene Expression during Liver Development.. Mol. Cell. Biol. 26: 6037-6046 [Abstract] [Full Text]  
  • Cheng, A., Zhang, M., Crosson, S. M., Bao, Z. Q., Saltiel, A. R. (2006). Regulation of the Mouse Protein Targeting to Glycogen (PTG) Promoter by the FoxA2 Forkhead Protein and by 3',5'-Cyclic Adenosine 5'-Monophosphate in H4IIE Hepatoma Cells. Endocrinology 147: 3606-3612 [Abstract] [Full Text]  
  • Miao, J., Fang, S., Bae, Y., Kemper, J. K. (2006). Functional Inhibitory Cross-talk between Constitutive Androstane Receptor and Hepatic Nuclear Factor-4 in Hepatic Lipid/Glucose Metabolism Is Mediated by Competition for Binding to the DR1 Motif and to the Common Coactivators, GRIP-1 and PGC-1{alpha}. J. Biol. Chem. 281: 14537-14546 [Abstract] [Full Text]  
  • Berg, D. T., Gerlitz, B., Sharma, G. R., Richardson, M. A., Stephens, E. J., Grubbs, R. L., Holmes, K. C., Fynboe, K., Montani, D., Cramer, M. S., Engle, S. D., Jakubowski, J. A., Heuer, J. G., Grinnell, B. W. (2006). FoxA2 Involvement in Suppression of Protein C, an Outcome Predictor in Experimental Sepsis.. CVI 13: 426-432 [Abstract] [Full Text]  
  • Kasper, L. H., Fukuyama, T., Biesen, M. A., Boussouar, F., Tong, C., de Pauw, A., Murray, P. J., van Deursen, J. M. A., Brindle, P. K. (2006). Conditional Knockout Mice Reveal Distinct Functions for the Global Transcriptional Coactivators CBP and p300 in T-Cell Development. Mol. Cell. Biol. 26: 789-809 [Abstract] [Full Text]  
  • Kim, I.-M., Zhou, Y., Ramakrishna, S., Hughes, D. E., Solway, J., Costa, R. H., Kalinichenko, V. V. (2005). Functional Characterization of Evolutionarily Conserved DNA Regions in Forkhead Box F1 Gene Locus. J. Biol. Chem. 280: 37908-37916 [Abstract] [Full Text]  
  • Rubins, N. E., Friedman, J. R., Le, P. P., Zhang, L., Brestelli, J., Kaestner, K. H. (2005). Transcriptional Networks in the Liver: Hepatocyte Nuclear Factor 6 Function Is Largely Independent of Foxa2. Mol. Cell. Biol. 25: 7069-7077 [Abstract] [Full Text]  
  • Kim, I.-M., Ramakrishna, S., Gusarova, G. A., Yoder, H. M., Costa, R. H., Kalinichenko, V. V. (2005). The Forkhead Box M1 Transcription Factor Is Essential for Embryonic Development of Pulmonary Vasculature. J. Biol. Chem. 280: 22278-22286 [Abstract] [Full Text]  
  • Kim, J.-Y., Kim, H.-J., Kim, K. T., Park, Y.-Y., Seong, H.-A, Park, K. C., Lee, I.-K., Ha, H., Shong, M., Park, S. C., Choi, H.-S. (2004). Orphan Nuclear Receptor Small Heterodimer Partner Represses Hepatocyte Nuclear Factor 3/Foxa Transactivation via Inhibition of Its DNA Binding. Mol. Endocrinol. 18: 2880-2894 [Abstract] [Full Text]  
  • Rausa, F. M. III, Hughes, D. E., Costa, R. H. (2004). Stability of the Hepatocyte Nuclear Factor 6 Transcription Factor Requires Acetylation by the CREB-binding Protein Coactivator. J. Biol. Chem. 279: 43070-43076 [Abstract] [Full Text]  
  • Sheng, W., Yan, H., Rausa, F. M. III, Costa, R. H., Liao, X. (2004). Structure of the Hepatocyte Nuclear Factor 6{alpha} and Its Interaction with DNA. J. Biol. Chem. 279: 33928-33936 [Abstract] [Full Text]  
  • Eeckhoute, J., Formstecher, P., Laine, B. (2004). Hepatocyte Nuclear Factor 4{alpha} enhances the Hepatocyte Nuclear Factor 1{alpha}-mediated activation of transcription. Nucleic Acids Res 32: 2586-2593 [Abstract] [Full Text]  
  • Major, M. L., Lepe, R., Costa, R. H. (2004). Forkhead Box M1B Transcriptional Activity Requires Binding of Cdk-Cyclin Complexes for Phosphorylation-Dependent Recruitment of p300/CBP Coactivators. Mol. Cell. Biol. 24: 2649-2661 [Abstract] [Full Text]  
  • Kalinichenko, V. V., Major, M. L., Wang, X., Petrovic, V., Kuechle, J., Yoder, H. M., Dennewitz, M. B., Shin, B., Datta, A., Raychaudhuri, P., Costa, R. H. (2004). Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 18: 830-850 [Abstract] [Full Text]