![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 56, Issue 4, 797-806, October 1999
B-Dependent Mechanism
Department of Molecular Biology (W.V.B., K.D.B., G.H.)
University of Gent and Flanders Interuniversity Institute for
Biotechnology, Gent, Belgium; and Hoechst Marion Roussel (E.F.,
M.R.-R.), Molecular and Cellular Biology, Bone Disease Group,
Romainville Cedex, France
Synthetic glucocorticoids (GCs) remain among the most effective agents
for the management of chronic inflammatory diseases. However, major
side effects severely limit their therapeutic use. Physiologic and
therapeutic activities of GCs are mediated by a nuclear receptor
belonging to a superfamily of ligand-inducible transcription factors
that, in addition to directly regulating their cognate gene programs,
can also mutually interfere with other signaling pathways. We recently
identified selective ligands of the glucocorticoid receptor that
dissociate transactivation from activator protein 1 transrepression, and most importantly retain in vivo anti-inflammatory
activity. To further document the mechanisms of action sustaining the
observed in vivo activity, we report here on the interference of
dissociated GCs with nuclear factor 
B (NF-B)-driven gene
activation. We show that dissociated GCs repress tumor necrosis
factor-induced interleukin-6 gene expression by an
NF-B-dependent mechanism, without changing the expression level of
inhibitor B. The DNA-binding activity of induced NF-B also
remained unchanged after stimulation of cells with the various compounds. Evidence for a direct nuclear mechanism of action was obtained by analysis of cell lines constitutively expressing a fusion
protein between the DNA-binding domain of the yeast Gal4 protein and
the transactivating p65 subunit of NF-B, which was able to
efficiently repress a Gal4-dependent luciferase reporter gene upon
addition of the dissociated compounds. We therefore conclude that, in
addition to dissociating transactivation from activator protein 1 transrepression, dissociated GCs mediate inhibition of NF-B
signaling by a mechanism that is independent of inhibitor B induction.
This article has been cited by other articles:
|
|
 |
|
  M. Hoekstra, I. Meurs, M. Koenders, R. Out, R. B. Hildebrand, J. K. Kruijt, M. Van Eck, and T. J. C. Van Berkel Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting J. Lipid Res., April 1, 2008; 49(4): 738 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Newton and N. S. Holden Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor? Mol. Pharmacol., October 1, 2007; 72(4): 799 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. I. Plotkin, S. C. Manolagas, and T. Bellido Glucocorticoids Induce Osteocyte Apoptosis by Blocking Focal Adhesion Kinase-mediated Survival: EVIDENCE FOR INSIDE-OUT SIGNALING LEADING TO ANOIKIS J. Biol. Chem., August 17, 2007; 282(33): 24120 - 24130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kaileh, W. Vanden Berghe, A. Heyerick, J. Horion, J. Piette, C. Libert, D. De Keukeleire, T. Essawi, and G. Haegeman Withaferin A Strongly Elicits I{kappa}B Kinase beta Hyperphosphorylation Concomitant with Potent Inhibition of Its Kinase Activity J. Biol. Chem., February 16, 2007; 282(7): 4253 - 4264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Chivers, W. Gong, E. M. King, J. Seybold, J. C. Mak, L. E. Donnelly, N. S. Holden, and R. Newton Analysis of the Dissociated Steroid RU24858 Does Not Exclude a Role for Inducible Genes in the Anti-Inflammatory Actions of Glucocorticoids Mol. Pharmacol., December 1, 2006; 70(6): 2084 - 2095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. De Bosscher, W. V. Berghe, I. M. E. Beck, W. Van Molle, N. Hennuyer, J. Hapgood, C. Libert, B. Staels, A. Louw, and G. Haegeman A fully dissociated compound of plant origin for inflammatory gene repression PNAS, November 1, 2005; 102(44): 15827 - 15832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Li, S. Wang, and T. D. Gelehrter Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-{beta} Action J. Biol. Chem., October 24, 2003; 278(43): 41779 - 41788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Stevens, H. Garside, A. Berry, C. Waters, A. White, and D. Ray Dissociation of Steroid Receptor Coactivator 1 and Nuclear Receptor Corepressor Recruitment to the Human Glucocorticoid Receptor by Modification of the Ligand-Receptor Interface: The Role of Tyrosine 735 Mol. Endocrinol., May 1, 2003; 17(5): 845 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Ma, H. H. Yang, K. Parker, S. Manyak, J. M. Friedman, C. Altamirano, Z.-q. Wu, M. J. Borad, M. Frantzen, E. Roussos, et al. The Proteasome Inhibitor PS-341 Markedly Enhances Sensitivity of Multiple Myeloma Tumor Cells to Chemotherapeutic Agents Clin. Cancer Res., March 1, 2003; 9(3): 1136 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lasa, S. M. Abraham, C. Boucheron, J. Saklatvala, and A. R. Clark Dexamethasone Causes Sustained Expression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase 1 and Phosphatase-Mediated Inhibition of MAPK p38 Mol. Cell. Biol., November 15, 2002; 22(22): 7802 - 7811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Korhonen, A. Lahti, M. Hamalainen, H. Kankaanranta, and E. Moilanen Dexamethasone Inhibits Inducible Nitric-Oxide Synthase Expression and Nitric Oxide Production by Destabilizing mRNA in Lipopolysaccharide-Treated Macrophages Mol. Pharmacol., September 1, 2002; 62(3): 698 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Delerive, K. De Bosscher, W. Vanden Berghe, J.-C. Fruchart, G. Haegeman, and B. Staels DNA Binding-Independent Induction of I{kappa}B{alpha} Gene Transcription by PPAR{alpha} Mol. Endocrinol., May 1, 2002; 16(5): 1029 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yoshikawa, Y. Makino, K. Okamoto, C. Morimoto, I. Makino, and H. Tanaka Distinct Interaction of Cortivazol with the Ligand Binding Domain Confers Glucocorticoid Receptor Specificity. CORTIVAZOL IS A SPECIFIC LIGAND FOR THE GLUCOCORTICOID RECEPTOR J. Biol. Chem., February 8, 2002; 277(7): 5529 - 5540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Miura, R. Ouchida, N. Yoshikawa, K. Okamoto, Y. Makino, T. Nakamura, C. Morimoto, I. Makino, and H. Tanaka Functional Modulation of the Glucocorticoid Receptor and Suppression of NF-kappa B-dependent Transcription by Ursodeoxycholic Acid J. Biol. Chem., December 7, 2001; 276(50): 47371 - 47378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. De Bosscher, W. Vanden Berghe, and G. Haegeman Glucocorticoid Repression of AP-1 Is Not Mediated by Competition for Nuclear Coactivators Mol. Endocrinol., February 1, 2001; 15(2): 219 - 227. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. G. Belvisi, S. L. Wicks, C. H. Battram, S. E. W. Bottoms, J. E. Redford, P. Woodman, T. J. Brown, S. E. Webber, and M. L. Foster Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity J. Immunol., February 1, 2001; 166(3): 1975 - 1982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Newton Molecular mechanisms of glucocorticoid action: what is important? Thorax, July 1, 2000; 55(7): 603 - 613. [Full Text]
|
|
|
|
|
|
K. De Bosscher, W. Vanden Berghe, L. Vermeulen, S. Plaisance, E. Boone, and G. Haegeman Glucocorticoids repress NF-kappa B-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell PNAS, April 11, 2000; 97(8): 3919 - 3924. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
