Ubiquitin: signal & proteosome inhibition
Developmental Biology and Cancer Research, Centre Antoine Lacassagne, Institute of Signaling
Accumulating evidence indicates that the proteasome, a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell cycle progression, apoptosis and adaptation to various stresses has become an important target for anticancer therapy. Before a protein is degraded, it receives a signature for destruction by the ubiquitin conjugation system, which constitutes in the attachment of a polyubiquitin chain on the target protein. The proteasome’s 19S regulatory cap binds the polyubiquitin chain, unfolds the protein, and delivers the protein into the proteasome’s proteolytic core. The proteolytic core is composed of 2 inner b rings and 2 outer a rings. The 2 b 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. The dipeptidyl boronic acid, bortezomib is a reversible proteasomal inhibitor that interacts with a threonine residue involved in the chymotryptic proteolytic activity. This action stops proteasomal function leading to cell cycle arrest and apoptosis. In in vitro and in vivo animal studies, inhibition of the proteasome with bortezomib (VELCADE; formerly, PS-341, LDP-341, and MLN341) resulted in antitumor activity against numerous tumor types either alone or in combination with conventional chemotherapeutic agents; these results provided the rationale for a broad program of clinical trials. Bortezomib is currently in phase III trials for treatment of myelomas and is in early clinical development for treatment of numerous other tumor types. In addition to providing another target for anticancer treatment, proteasomal inhibition may also provide a means to treat refractory tumors. In this presentation we will describe and discuss : i) the functional basis of the ubiquitin-dependent degradation systems, ii) the various mechanisms leading either to specific or to global inhibition of the proteosomal pathway, iii) the specific control of the Hypoxia-Inducible Factor-1a (HIF-1a) by proteasomes and iv) the rationale for antitumor therapy.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 701 (Molecular oncogenesis).