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Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York

Requests for reprints: Richard J.H. Wojcikiewicz, Department of Pharmacology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210-2339. Phone: 315-464-7956; Fax: 315-464-8014. E-mail: wojcikir{at}upstate.edu

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.

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Note: J.M. Webster is currently at Wadsworth Center, New York State Department of Health, Division of Genetic Disorders, 120 New Scotland Avenue, Albany, NY 12208.

Received 5/12/04; revised 7/16/04; accepted 8/13/04.

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