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Ubistatins Inhibit Proteasome-Dependent Degradation by Binding the Ubiquitin Chain
Rati Verma,1Noel R. Peters,2Mariapina D'Onofrio,3Gregory P. Tochtrop,2Kathleen M. Sakamoto,1,4Ranjani Varadan,3Mingsheng Zhang,5Philip Coffino,5David Fushman,3Raymond J. Deshaies,1Randall W. King2*
To identify previously unknown small molecules that inhibitcell cycle machinery, we performed a chemical genetic screenin Xenopus extracts. One class of inhibitors, termed ubistatins,blocked cell cycle progression by inhibiting cyclin B proteolysisand inhibited degradation of ubiquitinated Sic1 by purifiedproteasomes. Ubistatins blocked the binding of ubiquitinatedsubstrates to the proteasome by targeting the ubiquitin-ubiquitininterface of Lys48-linked chains. The same interface is recognizedby ubiquitin-chain receptors of the proteasome, indicating thatubistatins act by disrupting a critical protein-protein interactionin the ubiquitin-proteasome system.
1 Department of Biology, Howard Hughes Medical Institute (HHMI), California Institute of Technology, Pasadena, CA 91125, USA. 2 Institute of Chemistry and Cell Biology and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. 3 Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD 20742, USA. 4 Division of Hematology-Oncology, Mattel Children's Hospital, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California at Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. 5 Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143–0414, USA.
* To whom correspondence should be addressed. E-mail: randy_king{at}hms.harvard.edu
A New Small Molecule Inhibitor of Estrogen Receptor {alpha} Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells.
C. Mao, N. M. Patterson, M. T. Cherian, I. O. Aninye, C. Zhang, J. B. Montoya, J. Cheng, K. S. Putt, P. J. Hergenrother, E. M. Wilson, et al. (2008)
J. Biol. Chem.
283, 12819-12830
|Abstract »|Full Text »|PDF »
High-Throughput Bioluminescence Screening of Ubiquitin-Proteasome Pathway Inhibitors from Chemical and Natural Sources.
F. Ausseil, A. Samson, Y. Aussagues, I. Vandenberghe, L. Creancier, I. Pouny, A. Kruczynski, G. Massiot, and C. Bailly (2007)
J Biomol Screen
12, 106-116
|Abstract »|PDF »
Small Molecules, Big Players: the National Cancer Institute's Initiative for Chemical Genetics..
N. Tolliday, P. A. Clemons, P. Ferraiolo, A. N. Koehler, T. A. Lewis, X. Li, S. L. Schreiber, D. S. Gerhard, and S. Eliasof (2006)
Cancer Res.
66, 8935-8942
|Abstract »|Full Text »|PDF »
Bestatin, an Inhibitor of Aminopeptidases, Provides a Chemical Genetics Approach to Dissect Jasmonate Signaling in Arabidopsis.
W. Zheng, Q. Zhai, J. Sun, C.-B. Li, L. Zhang, H. Li, X. Zhang, S. Li, Y. Xu, H. Jiang, et al. (2006)
Plant Physiology
141, 1400-1413
|Abstract »|Full Text »|PDF »
Changes in Regulatory Phosphorylation of Cdc25C Ser287 and Wee1 Ser549 during Normal Cell Cycle Progression and Checkpoint Arrests.
