Ligand-Induced Estrogen Receptor α Degradation by the Proteasome: New Actors?

Abstract

In this perspective we consider new aspects of ligand-induced estrogen receptor α (ERα) degradation. What are the possible roles of CSN5/Jab1 and the CSN complex in this process? We compare hormone (estrogen) or pure antagonist (fulvestrant) induced degradation of ERα and review the effects of kinase-inhibitors and CRM1-dependent nuclear export on ERα degradation and transcription activation. A model for ERα action integrating these new actors is proposed and the relation between hormone-induced ERα degradation and transcription-activation is discussed. IntroductionOver the last few years, the involvement of the proteasome pathway in ligand-dependent nuclear receptor degradation has been established. This pathway entails first a polyubiquitination of the substrate, catalyzed by three factors (E1, E2 and E3), followed by its proteolysis by the proteasome. Recently, the role of the CSN complex that regulates the activity of a class of E3 ubiquitin ligases, the cullin RING ubiquitin ligase superfamily, was demonstrated. The cullin subunits of these ubiquitin ligases are modified by the conjugation of an ubiquitin-like protein, NEDD8. The neddylated subunit Cul1 is selectively degraded. Recent data demonstrate that CSN, via its subunit CSN5/Jab1, dennedylates cullin, thus increasing the activity of the E3 ligases [Wee et al., 2005].Several lines of evidence suggest that CSN is involved in ligand-dependant nuclear receptor degradation. First, estrogen receptor α (ERα) degradation is dependant on the neddylation pathway [Fan et al., 2003]; second, CSN5/Jab1 interacts with both the progesterone receptor and the coactivator SRC1 and is itself a coactivator of the nuclear receptors [Fan et al., 2003]; third, Jab1/CSN5 increases hormone-induced ERα degradation [Fan et al., 2003].The nature of the ligand affects ERα degradation differently: estradiol and the pure antagonist fulvestrant induce ERα degradation by the proteasome, whereas the mixed antagonist tamoxifen stabilizes Erα [Wijayaratne and McDonnell, 2001]. Thus, degradation may play an important role in ERα function and/or the action of its antagonists. ERα undergoes post translational modifications such as phosphorylation [Lannigan, 2003], acetylation [Wang et al., 2001] or sumoylation [Sentis et al., 2005]. However, the role of such modifications in targeting ERα for degradation remains unclear. A kinase activity, inhibited by curcumin, is associated to CSN. At least two curcumin-sensitive kinases, CKII and PKD, which co-purify with CSN, could contribute to this activity [Uhle et al., 2003]. CKII phosphorylates ERα on Ser167 in response to estradiol [Lannigan, 2003]. The inhibition of ERα degradation by curcumin and the co-immunoprecipitation of Jab1/CSN5 with ERα in the presence of curcumin, suggest that this kinase activity could participate in targeting ERα for degradation. In addition, the inhibition by curcumin of the interaction of ERα with its DNA target, points towards a role of this complex in transcription activation [Callige et al., 2005].The discove...

Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells

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