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 Towers, T. L.
Right arrow Articles by Freedman, L. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Towers, T. L.
Right arrow Articles by Freedman, L. P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 1999, p. 4191-4199, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Two-Hit Mechanism for Vitamin D3-Mediated Transcriptional Repression of the Granulocyte-Macrophage Colony-Stimulating Factor Gene: Vitamin D Receptor Competes for DNA Binding with NFAT1 and Stabilizes c-Jun

Terri L. Towers,1 Teodora P. Staeva,2 and Leonard P. Freedman1,*

Cell Biology Program1 and Immunology Program,2 Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Cornell University Graduate School of Medical Sciences, New York, New York 10021

Received 29 October 1998/Returned for modification 3 March 1999/Accepted 15 March 1999

We previously described a control element in the granulocyte-macrophage colony-stimulating factor (GM-CSF) enhancer that is necessary and sufficient to mediate both transcriptional activation in response to T-cell stimuli and transcriptional repression by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] through the vitamin D3 receptor (VDR). This DNA element is a composite site that is recognized by both Fos-Jun and NFAT1; it is directly bound by VDR in the absence of a retinoid X receptor as an apparent monomer, and it is bound in a unique tertiary conformation. We describe here the mechanism by which VDR elicits its transcriptional inhibitory effect. Firstly, VDR outcompetes NFAT1 for binding to the composite site. Overexpression of NFAT1 in vivo by transient transfection is able to relieve the 1,25(OH)2D3-dependent repression. Secondly, VDR stabilizes the binding of a Jun-Fos heterodimer to the adjacent AP-1 portion of the element. This appears to occur through a direct interaction between VDR and c-Jun, as demonstrated in vitro by direct glutathione S-transferase coprecipitation assays. In vivo, overexpression of c-Jun, but not c-Fos, leads to a rescue of the 1,25(OH)2D3-mediated repression. Transfected FLAG-VDR bound to the NFAT1-AP-1 DNA binding element can be selectively precipitated from nuclear extracts that are made from cells treated with activating agents in the presence of 1,25(OH)2D3. VDR is not detected in the complex in the absence of the ligand. Thus, VDR acts selectively on the two components required for activation of this promoter/enhancer: it competes with NFAT1 for binding to the composite site, positioning itself adjacent to Jun-Fos on the DNA. Co-occupancy apparently leads to an inhibitory effect on c-Jun's transactivation function. These two events mediated by VDR effectively block the NFAT1-AP-1 activation complex, resulting in an attenuation of activated GM-CSF transcription.

* Corresponding author. Mailing address: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Cornell University Graduate School of Medical Sciences, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2976. Fax: (212) 717-3298. E-mail: l-freedman{at}ski.mskcc.org.

Molecular and Cellular Biology, June 1999, p. 4191-4199, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Bouillon, R., Carmeliet, G., Verlinden, L., van Etten, E., Verstuyf, A., Luderer, H. F., Lieben, L., Mathieu, C., Demay, M. (2008). Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice. Endocr. Rev. 29: 726-776 [Abstract] [Full Text]  
  • Arnson, Y., Amital, H., Shoenfeld, Y. (2007). Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 66: 1137-1142 [Abstract] [Full Text]  
  • Li, Q.-P., Qi, X., Pramanik, R., Pohl, N. M., Loesch, M., Chen, G. (2007). Stress-induced c-Jun-dependent Vitamin D Receptor (VDR) Activation Dissects the Non-classical VDR Pathway from the Classical VDR Activity. J. Biol. Chem. 282: 1544-1551 [Abstract] [Full Text]  
  • Seoane, S., Perez-Fernandez, R. (2006). The Vitamin D Receptor Represses Transcription of the Pituitary Transcription Factor Pit-1 Gene without Involvement of the Retinoid X Receptor. Mol. Endocrinol. 20: 735-748 [Abstract] [Full Text]  
  • Dong, X., Lutz, W., Schroeder, T. M., Bachman, L. A., Westendorf, J. J., Kumar, R., Griffin, M. D. (2005). Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter. Proc. Natl. Acad. Sci. USA 102: 16007-16012 [Abstract] [Full Text]  
  • Hines, E. R., Kolek, O. I., Jones, M. D., Serey, S. H., Sirjani, N. B., Kiela, P. R., Jurutka, P. W., Haussler, M. R., Collins, J. F., Ghishan, F. K. (2004). 1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter. J. Biol. Chem. 279: 46406-46414 [Abstract] [Full Text]  
  • Bastie, J.-N., Balitrand, N., Guidez, F., Guillemot, I., Larghero, J., Calabresse, C., Chomienne, C., Delva, L. (2004). 1{alpha},25-Dihydroxyvitamin D3 Transrepresses Retinoic Acid Transcriptional Activity via Vitamin D Receptor in Myeloid Cells. Mol. Endocrinol. 18: 2685-2699 [Abstract] [Full Text]  
  • Koszewski, N. J., Alimov, A. P., Park-Sarge, O.-K., Malluche, H. H. (2004). Suppression of the Human Parathyroid Hormone Promoter by Vitamin D Involves Displacement of NF-Y Binding to the Vitamin D Response Element. J. Biol. Chem. 279: 42431-42437 [Abstract] [Full Text]  
  • Qi, X., Pramanik, R., Wang, J., Schultz, R. M., Maitra, R. K., Han, J., DeLuca, H. F., Chen, G. (2002). The p38 and JNK Pathways Cooperate to trans-Activate Vitamin D Receptor via c-Jun/AP-1 and Sensitize Human Breast Cancer Cells to Vitamin D3-induced Growth Inhibition. J. Biol. Chem. 277: 25884-25892 [Abstract] [Full Text]  
  • Benkoussa, M., Brand, C., Delmotte, M.-H., Formstecher, P., Lefebvre, P. (2002). Retinoic Acid Receptors Inhibit AP1 Activation by Regulating Extracellular Signal-Regulated Kinase and CBP Recruitment to an AP1-Responsive Promoter. Mol. Cell. Biol. 22: 4522-4534 [Abstract] [Full Text]  
  • Yang, X. Y., Wang, L. H., Mihalic, K., Xiao, W., Chen, T., Li, P., Wahl, L. M., Farrar, W. L. (2002). Interleukin (IL)-4 Indirectly Suppresses IL-2 Production by Human T Lymphocytes via Peroxisome Proliferator-activated Receptor gamma Activated by Macrophage-derived 12/15-Lipoxygenase Ligands. J. Biol. Chem. 277: 3973-3978 [Abstract] [Full Text]  
  • Cippitelli, M., Fionda, C., Di Bona, D., Di Rosa, F., Lupo, A., Piccoli, M., Frati, L., Santoni, A. (2002). Negative Regulation of CD95 Ligand Gene Expression by Vitamin D3 in T Lymphocytes. J. Immunol. 168: 1154-1166 [Abstract] [Full Text]  
  • Staeva-Vieira, T. P., Freedman, L. P. (2002). 1,25-Dihydroxyvitamin D3 Inhibits IFN-{gamma} and IL-4 Levels During In Vitro Polarization of Primary Murine CD4+ T Cells. J. Immunol. 168: 1181-1189 [Abstract] [Full Text]  
  • Smith, P. J., Cousins, D. J., Jee, Y.-K., Staynov, D. Z., Lee, T. H., Lavender, P. (2001). Suppression of Granulocyte-Macrophage Colony-Stimulating Factor Expression by Glucocorticoids Involves Inhibition of Enhancer Function by the Glucocorticoid Receptor Binding to Composite NF-AT/Activator Protein-1 Elements. J. Immunol. 167: 2502-2510 [Abstract] [Full Text]  
  • POLLY, P., HERDICK, M., MOEHREN, U., BANIAHMAD, A., HEINZEL, T., CARLBERG, C. (2000). VDR-Alien: a novel, DNA-selective vitamin D3 receptor-corepressor partnership. FASEB J. 14: 1455-1463 [Abstract] [Full Text]  
  • Webb, Y., Hermida-Matsumoto, L., Resh, M. D. (2000). Inhibition of Protein Palmitoylation, Raft Localization, and T Cell Signaling by 2-Bromopalmitate and Polyunsaturated Fatty Acids. J. Biol. Chem. 275: 261-270 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»