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 Reichardt, H. M.
Right arrow Articles by Schütz, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reichardt, H. M.
Right arrow Articles by Schütz, G.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2000, p. 9009-9017, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mice with an Increased Glucocorticoid Receptor Gene Dosage Show Enhanced Resistance to Stress and Endotoxic Shock

Holger M. Reichardt, Thorsten Umland, Anton Bauer, Oliver Kretz, and Günther Schütz*

Division of Molecular Biology of the Cell I, German Cancer Research Center, 69120 Heidelberg, Germany

Received 8 May 2000/Returned for modification 13 June 2000/Accepted 1 September 2000

Targeted mutagenesis of the glucocorticoid receptor has revealed an essential function for survival and the regulation of multiple physiological processes. To investigate the effects of an increased gene dosage of the receptor, we have generated transgenic mice carrying two additional copies of the glucocorticoid receptor gene by using a yeast artificial chromosome. Interestingly, overexpression of the glucocorticoid receptor alters the basal regulation of the hypothalamo-pituitary-adrenal axis, resulting in reduced expression of corticotropin-releasing hormone and adrenocorticotrope hormone and a fourfold reduction in the level of circulating glucocorticoids. In addition, primary thymocytes obtained from transgenic mice show an enhanced sensitivity to glucocorticoid-induced apoptosis. Finally, analysis of these mice under challenge conditions revealed that expression of the glucocorticoid receptor above wild-type levels leads to a weaker response to restraint stress and a strongly increased resistance to lipopolysaccharide-induced endotoxic shock. These results underscore the importance of tight regulation of glucocorticoid receptor expression for the control of physiological and pathological processes. Furthermore, they may explain differences in the susceptibility of humans to inflammatory diseases and stress, depending on individual prenatal and postnatal experiences known to influence the expression of the glucocorticoid receptor.

* Corresponding author. Mailing address: Division of Molecular Biology of the Cell I (A0200), German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 0049-6221-423411. Fax: 0049-6221-423470. E-mail: g.schuetz{at}dkfz.de.

Molecular and Cellular Biology, December 2000, p. 9009-9017, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Vreugdenhil, E., Verissimo, C. S. L., Mariman, R., Kamphorst, J. T., Barbosa, J. S., Zweers, T., Champagne, D. L., Schouten, T., Meijer, O. C., Ron de Kloet, E., Fitzsimons, C. P. (2009). MicroRNA 18 and 124a Down-Regulate the Glucocorticoid Receptor: Implications for Glucocorticoid Responsiveness in the Brain. Endocrinology 150: 2220-2228 [Abstract] [Full Text]  
  • Zhang, J., Ge, R., Matte-Martone, C., Goodwin, J., Shlomchik, W. D., Mamula, M. J., Kooshkabadi, A., Hardy, M. P., Geller, D. (2009). Characterization of a Novel Gain of Function Glucocorticoid Receptor Knock-in Mouse. J. Biol. Chem. 284: 6249-6259 [Abstract] [Full Text]  
  • Michailidou, Z., Carter, R. N., Marshall, E., Sutherland, H. G., Brownstein, D. G., Owen, E., Cockett, K., Kelly, V., Ramage, L., Al-Dujaili, E. A. S., Ross, M., Maraki, I., Newton, K., Holmes, M. C., Seckl, J. R., Morton, N. M., Kenyon, C. J., Chapman, K. E. (2008). Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet. FASEB J. 22: 3896-3907 [Abstract] [Full Text]  
  • Diefenbacher, M., Sekula, S., Heilbock, C., Maier, J. V., Litfin, M., van Dam, H., Castellazzi, M., Herrlich, P., Kassel, O. (2008). Restriction to Fos Family Members of Trip6-Dependent Coactivation and Glucocorticoid Receptor-Dependent Trans-Repression of Activator Protein-1. Mol. Endocrinol. 22: 1767-1780 [Abstract] [Full Text]  
  • Cooper, M. S., Stewart, P. M. (2007). Adrenal Insufficiency in Critical Illness. J Intensive Care Med 22: 348-362 [Abstract]  
  • Meyers, J. A., Taverna, J., Chaves, J., Makkinje, A., Lerner, A. (2007). Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells. Clin. Cancer Res. 13: 4920-4927 [Abstract] [Full Text]  
  • Michailidou, Z., Coll, A. P, Kenyon, C. J, Morton, N. M, O'Rahilly, S., Seckl, J. R, Chapman, K. E (2007). Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone. J Endocrinol 194: 161-170 [Abstract] [Full Text]  
  • Flaster, H., Bernhagen, J., Calandra, T., Bucala, R. (2007). The Macrophage Migration Inhibitory Factor-Glucocorticoid Dyad: Regulation of Inflammation and Immunity. Mol. Endocrinol. 21: 1267-1280 [Abstract] [Full Text]  
  • Brandt, J. v. d., Luhder, F., McPherson, K. G., de Graaf, K. L., Tischner, D., Wiehr, S., Herrmann, T., Weissert, R., Gold, R., Reichardt, H. M. (2007). Enhanced Glucocorticoid Receptor Signaling in T Cells Impacts Thymocyte Apoptosis and Adaptive Immune Responses. Am. J. Pathol. 170: 1041-1053 [Abstract] [Full Text]  
  • Baserga, M., Hale, M. A., McKnight, R. A., Yu, X., Callaway, C. W., Lane, R. H. (2005). Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289: R1348-R1353 [Abstract] [Full Text]  
  • Ridder, S., Chourbaji, S., Hellweg, R., Urani, A., Zacher, C., Schmid, W., Zink, M., Hortnagl, H., Flor, H., Henn, F. A., Schutz, G., Gass, P. (2005). Mice with Genetically Altered Glucocorticoid Receptor Expression Show Altered Sensitivity for Stress-Induced Depressive Reactions. J. Neurosci. 25: 6243-6250 [Abstract] [Full Text]  
  • van den Brandt, J., Kwon, S.-H., Hunig, T., McPherson, K. G., Reichardt, H. M. (2005). Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection. J. Immunol. 174: 7845-7852 [Abstract] [Full Text]  
  • Wang, X., DeFranco, D. B. (2005). Alternative Effects of the Ubiquitin-Proteasome Pathway on Glucocorticoid Receptor Down-Regulation and Transactivation Are Mediated by CHIP, an E3 Ligase. Mol. Endocrinol. 19: 1474-1482 [Abstract] [Full Text]  
  • Pazirandeh, A., Jondal, M., Okret, S. (2005). Conditional Expression of a Glucocorticoid Receptor Transgene in Thymocytes Reveals a Role for Thymic-Derived Glucocorticoids in Thymopoiesis in Vivo. Endocrinology 146: 2501-2507 [Abstract] [Full Text]  
  • Bai, Y., Onuma, H., Bai, X., Medvedev, A. V., Misukonis, M., Weinberg, J. B., Cao, W., Robidoux, J., Floering, L. M., Daniel, K. W., Collins, S. (2005). Persistent Nuclear Factor-{kappa}B Activation in Ucp2-/- Mice Leads to Enhanced Nitric Oxide and Inflammatory Cytokine Production. J. Biol. Chem. 280: 19062-19069 [Abstract] [Full Text]  
  • Ismaili, N., Blind, R., Garabedian, M. J. (2005). Stabilization of the Unliganded Glucocorticoid Receptor by TSG101. J. Biol. Chem. 280: 11120-11126 [Abstract] [Full Text]  
  • Cho, S., Kagan, B. L., Blackford, J. A. Jr., Szapary, D., Simons, S. S. Jr. (2005). Glucocorticoid Receptor Ligand Binding Domain Is Sufficient for the Modulation of Glucocorticoid Induction Properties by Homologous Receptors, Coactivator Transcription Intermediary Factor 2, and Ubc9. Mol. Endocrinol. 19: 290-311 [Abstract] [Full Text]  
  • Freeman, A. I, Munn, H. L, Lyons, V., Dammermann, A., Seckl, J. R, Chapman, K. E (2004). Glucocorticoid down-regulation of rat glucocorticoid receptor does not involve differential promoter regulation. J Endocrinol 183: 365-374 [Abstract] [Full Text]  
  • Barr, C. S., Newman, T. K., Schwandt, M., Shannon, C., Dvoskin, R. L., Lindell, S. G., Taubman, J., Thompson, B., Champoux, M., Lesch, K. P., Goldman, D., Suomi, S. J., Higley, J. D. (2004). Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. Proc. Natl. Acad. Sci. USA 101: 12358-12363 [Abstract] [Full Text]  
  • Pazirandeh, A., Jondal, M., Okret, S. (2004). Glucocorticoids Delay Age-Associated Thymic Involution through Directly Affecting the Thymocytes. Endocrinology 145: 2392-2401 [Abstract] [Full Text]  
  • van den Brandt, J., Wang, D., Reichardt, H. M. (2004). Resistance of Single-Positive Thymocytes to Glucocorticoid-Induced Apoptosis Is Mediated by CD28 Signaling. Mol. Endocrinol. 18: 687-695 [Abstract] [Full Text]  
  • Wang, Z., Garabedian, M. J. (2003). Modulation of Glucocorticoid Receptor Transcriptional Activation, Phosphorylation, and Growth Inhibition by p27Kip1. J. Biol. Chem. 278: 50897-50901 [Abstract] [Full Text]  
  • Nolan, L. A., Levy, A. (2003). Temporally Sensitive Trophic Responsiveness of the Adrenalectomized Rat Anterior Pituitary to Dexamethasone Challenge: Relationship between Mitotic Activity and Apoptotic Sensitivity. Endocrinology 144: 212-219 [Abstract] [Full Text]  
  • Wang, X., Pongrac, J. L., DeFranco, D. B. (2002). Glucocorticoid Receptors in Hippocampal Neurons that Do Not Engage Proteasomes Escape from Hormone-Dependent Down-Regulation but Maintain Transactivation Activity. Mol. Endocrinol. 16: 1987-1998 [Abstract] [Full Text]  
  • Smith, J. B., Nguyen, T. T., Hughes, H. J., Herschman, H. R., Widney, D. P., Bui, K. C., Rovai, L. E. (2002). Glucocorticoid-attenuated response genes induced in the lung during endotoxemia. Am. J. Physiol. Lung Cell. Mol. Physiol. 283: L636-L647 [Abstract] [Full Text]  
  • Brewer, J. A., Sleckman, B. P., Swat, W., Muglia, L. J. (2002). Green Fluorescent Protein-Glucocorticoid Receptor Knockin Mice Reveal Dynamic Receptor Modulation During Thymocyte Development. J. Immunol. 169: 1309-1318 [Abstract] [Full Text]  
  • DeFranco, D. B. (2002). Navigating Steroid Hormone Receptors through the Nuclear Compartment. Mol. Endocrinol. 16: 1449-1455 [Abstract] [Full Text]  
  • Sengupta, S., Wasylyk, B. (2001). Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. Genes Dev. 15: 2367-2380 [Abstract] [Full Text]  
  • Song, L.-N., Huse, B., Rusconi, S., Simons, S. S. Jr. (2001). Transactivation Specificity of Glucocorticoid Versus Progesterone Receptors. ROLE OF FUNCTIONALLY DIFFERENT INTERACTIONS OF TRANSCRIPTION FACTORS WITH AMINO- AND CARBOXYL-TERMINAL RECEPTOR DOMAINS. J. Biol. Chem. 276: 24806-24816 [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»