Bortezomib rapidly suppresses ubiquitin thiolesterification to ubiquitin-conjugating enzymes and inhibits ubiquitination of histones and type I inositol 1,4,5-trisphosphate receptor.
The proteasome inhibitor bortezomib is an emerging anticancer agent. Although the proteasome is clearly its locus of action, the early biochemical consequences of bortezomib treatment are poorly defined. Here, we show in cultured cells that bortezomib and other proteasome inhibitors rapidly inhibit free ubiquitin levels and ubiquitin thiolesterification to ubiquitin-conjugating enzymes. Inhibition of thiolesterification correlated with a reduction in the ubiquitination of certain substrates, exemplified by a dramatic decline in histone monoubiquitination and a decrease in the rate of inositol 1,4,5-trisphosphate receptor polyubiquitination. Thus, in addition to the expected effect of blocking the degradation of polyubiquitinated substrates, bortezomib can also inhibit ubiquitination. The effect of bortezomib on histone monoubiquitination may contribute to its therapeutic actions.
Department of Pharmacology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210-2339, USA.
Qun
Q
Xu
Michelle
M
Farah
Jack M
JM
Webster
Richard J H
RJ
Wojcikiewicz
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015220:Calcium Channels / Q000737:chemistry*; D002460:Cell Line; D002478:Cells, Cultured; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011485:Protein Binding; D011719:Pyrazines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D006657:Histones; D020672:I-kappa B Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D018160:Receptors, Cytoplasmic and Nuclear; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D044763:Ubiquitin-Conjugating Enzymes; D004229:Dithiothreitol