Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

Abstract

SRC-3 is an important coactivator of nuclear receptors including the retinoic acid (RA) receptor α. Most of SRC-3 functions are facilitated by changes in the posttranslational code of the protein that involves mainly phosphorylation and ubiquitination. We recently reported that SRC-3 is degraded by the proteasome in response to RA. Here, by using an RNAi E3-ubiquitin ligase entry screen, we identified CUL-3 and RBX1 as components of the E3 ubiquitin ligase involved in the RA-induced ubiquitination and subsequent degradation of SRC-3. We also show that the RA-induced ubiquitination of SRC-3 depends on its prior phosphorylation at serine 860 that promotes binding of the CUL-3–based E3 ligase in the nucleus. Finally, phosphorylation, ubiquitination, and degradation of SRC-3 cooperate to control the dynamics of transcription. In all, this process participates to the antiproliferative effect of RA.

Retinoids induce stem cell differentiation via epigenetic changes

“…The nuclear receptor interaction domains (NRID) of co-activator proteins contain three highly conserved motifs with a consensus amino acid sequence L XX LL; such L XX LL motifs mediate direct interaction with the AF-2 domain of RARs upon ligand binding [10]. Ncoa3 ubiquitination is also controlled by RA, and Ncoa3 degradation is involved both in the transcription of RA target genes and in the growth inhibitory actions of RA [11]. Binding of Ncoa3 then allows p300 (GC22P041487, KAT3B) and the related protein CBP (GC03P020081, KAT2B, P/CAF, GCN5, CREB Binding protein) to bind at the transcriptional activation complex.…”

Steroid receptor coactivator-3 as a potential molecular target for cancer therapy

“…REGγ, 20S proteasome regulator, can also interact with SRC-3 and mediates its turnover in an ubiquitin-independent manner 79 . Recently, the components of E3 ligase, CUL1 and RBX1, were shown to be involved in SRC-3 ubiquitinylation and degradation, in response to retinoid acid treatment 80 . CHIP (carboxyl terminus of Hsc70-interacting protein) is a U-box-type ubiquitin ligase that induces ubiquitinylation and degradation of its substrates.…”

Vitamin A and retinoid signaling: genomic and nongenomic effects

“…The coactivator SRC-3 is also phosphorylated ( 148 ), resulting in its dissociation from RARs. Then phosphorylation marks SRC-3 for ubiquitination and degradation by the proteasome ( 149 ). It has been proposed that this ubiquitinationdegradation process would facilitate the dynamics of RAR-mediated transcription via allowing other coregulators to bind.…”