Potentiation of Glucocorticoid Receptor Transcriptional Activity by Sumoylation

Abstract

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.

Sumoylation of the net inhibitory domain (NID) is stimulated by PIAS1 and has a negative effect on the transcriptional activity of Net

“…However, we cannot exclude that there are effects that are not detected in our assays. Such effects could be promoter context dependent, as has been observed for C/EBPa (Subramanian et al, 2003) and the glucocorticoid receptor (Le Drean et al, 2002).…”

“…In a number of other studies, SUMO modification has been found to correlate with either repression or attenuation of activation of transcription, and in certain cases the sumoylation sites have been shown to map to autologous repression domains (for a review, see Verger et al, 2003). However, less frequently, sumoylation has been shown to stimulate the activity of transcription factors (Le Drean et al, 2002;Nishida and Yasuda, 2002), possibly because of indirect effects. Our results would fit into a general model that is emerging to account for PIAS/SUMO-mediated repression (for reviews, see Melchior et al, 2003;Schmidt and Muller, 2003;Seeler and Dejean, 2003;Verger et al, 2003;Johnson, 2004;Muller et al, 2004).…”

The Protein Stability and Transcriptional Activity of p63α are Regulated by SUMO-1 Conjugation

“…The same type of regulation by SUMO-1 has been shown to occur also for the Glucorticoid Receptor and for the Peroxisome Proliferator-Activated Receptor γ2 in which SUMO-1 conjugation dictates protein instabilty through the proteasome. 46,47 The TAα p63 isoform, although containing the SUMO-1 site, was found to be unaffected by SUMO-1 overexpression; this is possibly due to the inhibitory domain mapped in the last 71 amino acids within the α C terminus that was…”

SUMO: a regulator of gene expression and genome integrity

“…Remarkably, PIAS proteins stimulate the modification of AR, GR and PR (Kotaja et al, 2002b;Nishida and Yasuda, 2002). It is noteworthy, however, that in some contexts, the SUMO system has been shown to activate steroid receptors (Le Drean et al, 2002). This is most likely due to the modification of the nuclear receptor coactivators of the p160 family, such as Grip1/TIF2 and SRC-1 (Jimenez-Lara et al, 2002; Kotaja et al, 2002a;Chauchereau et al, 2003).…”