The ubiquitin-proteasome pathway (UPP) constitutes the major pathway for degradation of nuclear and cytoplasmic proteins in the eukaryotic cell. The role of the UPP in cell cycle progression and signal transduction pathways is well known, but its role in nuclear hormone receptor (NHR) functions is a surprise to many scientists. The involvement of a number of UPP components in NHR-mediated transcription suggested a possible link between these two diverse pathways. Both NHRs and their coregulators (coactivators and corepressors) are ubiquitinated and degraded by the UPP. Interestingly, the UPP enzymes and components of both the 19S and 20S proteasomes are recruited to NHR target gene promoters suggesting that the UPP could be involved in NHR transcription regulation at multiple steps. In recent years, it has been demonstrated that the role of ubiquitin can be expanded well beyond its function of acting as a death-tag for the degradation of proteins by the 26S proteasome. Keeping in mind the involvement of the UPP in a variety of cellular processes, its deregulation or malfunction has been associated with a number of human diseases including cancers. Targeting the UPP as a potential for drug discovery in the treatment of cancer and neurodegenerative disorders is just beginning. In this chapter, we will discuss the probable role of the UPP in NHR regulated gene transcription and also the possibility of targeting the UPP for drug discovery for the treatment of endocrine cancers like breast and prostate cancers.
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