This Article Full Text Full Text (PDF) 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 NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Holmstrom, S. R. Articles by Iñiguez-Lluhí, J. A. Search for Related Content PubMed PubMed Citation Articles by Holmstrom, S. R. Articles by Iñiguez-Lluhí, J. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

SUMO-Mediated Inhibition of Glucocorticoid Receptor Synergistic Activity Depends on Stable Assembly at the Promoter But Not on DAXX

Department of Pharmacology (S.R.H., S.C., J.A.I-L.), University of Michigan Medical School, Ann Arbor, Michigan 48109-0632; and Department of Cellular and Molecular Pharmacology (A.Y.-L.S.), University of California, San Francisco, San Francisco, California 94143-2280

Address all correspondence and requests for reprints to: Jorge A. Iñiguez-Lluhí, Department of Pharmacology, University of Michigan Medical School. Ann Arbor, Michigan 48109-0632. E-mail: iniguez{at}umich.edu.

Multiple transcription factors, including members of the nuclear receptor family, harbor one or more copies of a short regulatory motif that limits synergistic transactivation in a context-dependent manner. These synergy control (SC) motifs exert their effects by serving as sites for posttranslational modification by small ubiquitin-like modifier (SUMO) proteins. By analyzing the requirements for both synergy control and SUMOylation in the glucocorticoid receptor (GR), we find that an intact ligand-binding domain and an engaged DNA- binding domain dimerization interface are necessary for effective synergy control. However, these features, which promote stable assembly of GR-DNA complexes, are required downstream of SUMOylation because their disruption or deletion does not interfere with SUMO modification. Remarkably, in the absence of these features, sensitivity to the effects of SUMOylation can be restored simply by stabilization of DNA interactions through a heterologous DNA binding domain. The data indicate that stable interaction with DNA is an important prerequisite for SUMO-dependent transcriptional inhibition. Analysis of genomic regions occupied by GR indicates that the effects of SC motif SUMOylation are most evident at multiple, near-ideal GR binding sites and that SUMOylation selectively affects the induction of linked endogenous genes. Although the SUMO-binding protein DAXX has been proposed to mediate the inhibitory effects of GR SUMOylation, we find that inhibition by DAXX is independent of GR SUMOylation. Furthermore, neither expression nor knockdown of DAXX influences SUMO effects on GR. We therefore propose that stable binding of GR to multiple sites on DNA allows for the SUMO-dependent recruitment of inhibitory factors distinct from DAXX.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Ligands:   Dexamethasone

This article has been cited by other articles:

				S. Mukherjee, M. Thomas, N. Dadgar, A. P. Lieberman, and J. A. Iniguez-Lluhi Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation J. Biol. Chem., August 7, 2009; 284(32): 21296 - 21306. [Abstract] [Full Text] [PDF]

				H. Abdel-Hafiz, M. L. Dudevoir, and K. B. Horwitz Mechanisms Underlying the Control of Progesterone Receptor Transcriptional Activity by SUMOylation J. Biol. Chem., April 3, 2009; 284(14): 9099 - 9108. [Abstract] [Full Text] [PDF]

				S. Kaikkonen, T. Jaaskelainen, U. Karvonen, M. M. Rytinki, H. Makkonen, D. Gioeli, B. M. Paschal, and J. J. Palvimo SUMO-Specific Protease 1 (SENP1) Reverses the Hormone-Augmented SUMOylation of Androgen Receptor and Modulates Gene Responses in Prostate Cancer Cells Mol. Endocrinol., March 1, 2009; 23(3): 292 - 307. [Abstract] [Full Text] [PDF]

				L. A. Campbell, E. J. Faivre, M. D. Show, J. G. Ingraham, J. Flinders, J. D. Gross, and H. A. Ingraham Decreased Recognition of SUMO-Sensitive Target Genes following Modification of SF-1 (NR5A1) Mol. Cell. Biol., December 15, 2008; 28(24): 7476 - 7486. [Abstract] [Full Text] [PDF]