The proteasome: structure, function, and role in the cell - PubMed (original) (raw)

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The proteasome: structure, function, and role in the cell

Julian Adams. Cancer Treat Rev. 2003 May.

Abstract

The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis, and has therefore become an important target for anticancer therapy. Before a protein is degraded, it is first flagged for destruction by the ubiquitin conjugation system, which ultimately results in the attachment of a polyubiquitin chain on the target protein. The proteasome's 19S regulatory cap binds the polyubiquitin chain, denatures the protein, and feeds the protein into the proteasome's proteolytic core. The proteolytic core is composed of 2 inner beta rings and 2 outer alpha rings. The 2 beta rings each contain 3 proteolytic sites named for their trypsin-like, post-glutamyl peptide hydrolase-like (PGPH) (i.e., caspase-like), or chymotrypsin-like activity. Inhibition of the proteasome results in cell-cycle arrest and apoptosis. In in vitro and in vivo animal studies, inhibition of the proteasome via bortezomib (VELCADE; formerly, PS-341, LDP-341, and MLN341) had antitumor activity against numerous tumor types either alone or in combination with conventional chemotherapeutic agents; these results provided the rationale for a broad clinical trial program. Bortezomib is currently in phase III trials for myeloma and is in early clinical development for numerous other tumor types.

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