Noncompetitive Proteasome inhibition on Bortezomib resistance

Abstract

The proteasomal degradation pathway rids cells of excess and misfolded proteins and regulates the cellular levels of proteins that are responsible for processes, such as cell cycle progression, DNA repair, and transcription [reviewed in (1)]. The proteasomal pathway of protein degradation is initiated by the sequential enzymatic activities of ubiquitin ligases E1, E2, and E3, which add chains of ubiquitin molecules onto the lysine residues of proteins to mark them for degradation [reviewed in (2,3)]. Ubiquitintagged proteins are degraded by the 26S proteasome, a multimeric enzyme complex consisting of a and b subunits located in the nucleus and cytoplasm. Chemical and peptidyl inhibitors of the proteasome prevent ubiquitin-mediated protein degradation. In vitro and in vivo studies demonstrate that proteasome inhibitors induce cell death in malignant cells and inhibit tumor growth in mouse models of malignancy (4), thus supporting the development of proteasome inhibitors as therapeutic agents for the treatment of malignancies. All chemical proteasome inhibitors currently approved or under clinical evaluation, such as bortezomib and NPI-0052, bind threonine residues in the active sites of the b subunits of the 20S proteasome (the core complex of the 26S proteasome in eukaryotes, which degrades ubiquitinated target molecules in an Article

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@inproceedings{Li2010NoncompetitivePI, title={Noncompetitive Proteasome inhibition on Bortezomib resistance}, author={Xiaoming Li and Tabitha E. Wood and Remco Sprangers and Gerrit Jansen and Niels E. Franke and Xinliang Mao and Xiaoming Wang and Yi Zhang and Sue Ellen Verbrugge and Hans Adomat and Zhi Hua Li and Suzanne Trudel and Christine Chen and Tomasz L. Religa and Nazir Jamal and Hans Messner and Jacqueline Cloos and David R. Rose and Ami Navon and Emma Guns and Robert A. Batey and Lewis E. Kay and Aaron D. Schimmer}, year={2010} }