Published October 1, 2004
| Erratum + Supplemental Material
Journal Article
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Ubistatins Inhibit Proteasome-Dependent Degradation by Binding the Ubiquitin Chain
Chicago
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Abstract
To identify previously unknown small molecules that inhibit cell cycle machinery, we performed a chemical genetic screen in Xenopus extracts. One class of inhibitors, termed ubistatins, blocked cell cycle progression by inhibiting cyclin B proteolysis and inhibited degradation of ubiquitinated Sic1 by purified proteasomes. Ubistatins blocked the binding of ubiquitinated substrates to the proteasome by targeting the ubiquitin-ubiquitin interface of Lys^(48)-linked chains. The same interface is recognized by ubiquitin-chain receptors of the proteasome, indicating that ubistatins act by disrupting a critical protein-protein interaction in the ubiquitin-proteasome system.
Additional Information
© 2004 American Association for the Advancement of Science. 1 June 2004; accepted 6 August 2004. We thank the Developmental Therapeutics Program, National Cancer Institute, for providing access to compound collections, C. Pickart for tetraubiquitin chains of defined linkages, A. Salic for recombinant Axin and β-catenin-luciferase, and C. Sawyers for ARGFP. G.T. is supported by NIH National Research Service Award GM068276. K.M.S. is supported by a UCLA Specialized Programs of Research Excellence in Prostate Cancer Development Research Seed Grant (P50 CA92131), U.S. Department of Defense (DAMD17-03- 1-0220), and NIH (R21CA108545). P.C. is supported by NIH R01 GM-45335. D.F. is supported by NIH grant GM65334. R.J.D. is supported by HHMI and the Susan G. Komen Breast Cancer Foundation (DISS0201703). R.W.K. is supported by the NIH (CA78048 and GM66492), the McKenzie Family Foundation, and the Harvard-Armenise Foundation and is a Damon Runyon Scholar. Screening facilities at the Harvard Institute of Chemistry and Cell Biology were supported by grants from the Keck Foundation, Merck and Company, and Merck KGaA. R.J.D. is a founder and paid consultant of Proteolix, which is negotiating with Caltech and Harvard to license a patent related to ubistatin. Molecular interaction data have been deposited in the Biomolecular Interaction Network Database with accession codes 151787 to 151791.Attached Files
Supplemental Material - Verma._SOM2.pdf
Erratum - Verma_2008p874.pdf
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Additional details
- Eprint ID
- 51961
- DOI
- 10.1126/science.1100946
- Resolver ID
- CaltechAUTHORS:20141119-110723281
- NIH
- GM068276
- UCLA Specialized Programs of Research Excellence in Prostate Cancer Development Research Seed Grant
- P50 CA92131
- Department of Defense
- DAMD17-03-1-0220
- NIH
- R21CA108545
- NIH
- R01 GM-45335
- NIH
- GM65334
- Howard Hughes Medical Institute (HHMI)
- Susan G. Komen Breast Cancer Foundation
- DISS0201703
- NIH
- CA78048
- NIH
- GM66492
- McKenzie Family Foundation
- Harvard-Armenise Foundation
- Damon Runyon Scholar
- W. M. Keck Foundation
- Merck and Company
- Merck KGaA
- Created
-
2014-11-19Created from EPrint's datestamp field
- Updated
-
2023-10-18Created from EPrint's last_modified field