Nuclear hormone receptor degradation and gene transcription: an update

The ubiquitin-proteasome pathway (UPP) is known to degrade short-lived and misfolded proteins. Its role in cell cycle regulation and signal transduction is well established. However, the importance of the UPP in nuclear hormone receptor-regulated gene transcription is relatively new. Nuclear hormone receptors (NHRs) are degraded by the UPP both in the presence or absence of their cognate ligands. In recent years, it has become evident that NHR degradation and NHR-dependent transcription are interdependent processes. The link between these two processes has become stronger with the discovery of a number of ubiquitin-pathway enzymes and components of the proteasome acting as modulators of NHR function. Also, UPP enzymes and components of the proteasome are recruited to the promoters of NHR-responsive genes. Interestingly both coactivators and corepressors (coregulators) of NHRs are also targeted to the UPP for degradation. Furthermore, additional evidence also indicates that the UPP may be involved in the turnover of transcription complexes, thereby facilitating proper gene transcription. In this review we discuss and provide an update on the role of UPP in NHR-dependent gene regulation.