SUMO-Mediated Inhibition of Glucocorticoid Receptor Synergistic Activity Depends on Stable Assembly at the Promoter But Not on DAXX
Open Access
- 1 September 2008
- journal article
- other
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 22 (9), 2061-2075
- https://doi.org/10.1210/me.2007-0581
Abstract
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.Keywords
This publication has 80 references indexed in Scilit:
- Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid ReceptorPLoS Genetics, 2007
- Role of SUMO-Interacting Motif in Daxx SUMO Modification, Subnuclear Localization, and Repression of Sumoylated Transcription FactorsMolecular Cell, 2006
- Coordinated Regulation of AIB1 Transcriptional Activity by Sumoylation and PhosphorylationPublished by Elsevier BV ,2006
- Polycistronic RNA polymerase II expression vectors for RNA interference based on BIC/miR-155Nucleic Acids Research, 2006
- Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modificationsGenes & Development, 2006
- Insights into E3 ligase activity revealed by a SUMO–RanGAP1–Ubc9–Nup358 complexNature, 2005
- Structural Basis for E2-Mediated SUMO Conjugation Revealed by a Complex between Ubiquitin-Conjugating Enzyme Ubc9 and RanGAP1Cell, 2002
- Interaction of Daxx, a Fas Binding Protein, with Sentrin and Ubc9Biochemical and Biophysical Research Communications, 2000
- Cooperativity and Dimerization of Recombinant Human Estrogen Receptor Hormone-binding DomainPublished by Elsevier BV ,1997
- Determinants of high-affinity DNA binding by the glucocorticoid receptor: evaluation of receptor domains outside the DNA-binding domainBiochemistry, 1992