Potentiation of glucocorticoid receptor transcriptional activity by sumoylation.
The glucocorticoid receptor (GR) is a transcription factor, subject to several types of posttranslational modifications including phosphorylation and ubiquitination. We showed that the GR is covalently modified by the small ubiquitin-related modifier-1 (SUMO-1) peptide in mammalian cells. We demonstrated that GR sumoylation is not dependent on the presence of the ligand and regulates the stability of the protein as well as its transcriptional activity. SUMO-1 overexpression induces dramatic GR degradation, abolished by proteasome inhibition. We also found that SUMO-1 stimulates the transactivation capacity of GRs to an extent largely exceeding those observed so far for other sumoylated transcription factors. Overexpression of SUMO-1 specifically enhances the ligand-induced transactivation of GR up to 8-fold. However, this hyperactivation occurs only in the context of a synergy between multiple molecules of GRs. It requires more than one receptor DNA-binding site in promoter and becomes more prominent as the number of sites increases. Interestingly, these observations may be related to the transcriptional properties of the synergy control region of GRs, which precisely contains two evolutionary conserved sumoylation sites. We propose a model in which SUMO-1 regulates the synergy control function of GR and serves as a unique signal for activation and destruction.
Le Drean
Yves
Y
Information et Programmation Cellulaire, Unité Mixte de Recherche 6026 Centre National de la Recherche Scientifique, University of Rennes I, Rennes 35 042, France. yves.le-drean@univ-rennes1.fr
Mincheneau
Nathalie
N
Le Goff
Pascale
P
Michel
Denis
D
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D019556:COS Cells; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004355:Drug Stability; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D004247:DNA