Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 306 (5693): 117-120

Copyright © 2004 by the American Association for the Advancement of Science

Ubistatins Inhibit Proteasome-Dependent Degradation by Binding the Ubiquitin Chain

Rati Verma,1 Noel R. Peters,2 Mariapina D'Onofrio,3 Gregory P. Tochtrop,2 Kathleen M. Sakamoto,1,4 Ranjani Varadan,3 Mingsheng Zhang,5 Philip Coffino,5 David Fushman,3 Raymond J. Deshaies,1 Randall W. King2*

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 Lys48-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.

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Deubiquitinase Inhibition of 19S Regulatory Particles by 4-Arylidene Curcumin Analog AC17 Causes NF-{kappa}B Inhibition and p53 Reactivation in Human Lung Cancer Cells.
B. Zhou, Y. Zuo, B. Li, H. Wang, H. Liu, X. Wang, X. Qiu, Y. Hu, S. Wen, J. Du, et al. (2013)
Mol. Cancer Ther. 12, 1381-1392
   Abstract »    Full Text »    PDF »
A Modified HSP70 Inhibitor Shows Broad Activity as an Anticancer Agent.
G. M. Balaburski, J. I.- J. Leu, N. Beeharry, S. Hayik, M. D. Andrake, G. Zhang, M. Herlyn, J. Villanueva, R. L. Dunbrack Jr, T. Yen, et al. (2013)
Mol. Cancer Res. 11, 219-229
   Abstract »    Full Text »    PDF »
Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications.
S. Fulda, K. Rajalingam, and I. Dikic (2012)
EMBO Mol Med. 4, 545-556
   Abstract »    Full Text »    PDF »
Gold nanoparticles as a platform for creating a multivalent poly-SUMO chain inhibitor that also augments ionizing radiation.
Y.-J. Li, A. L. Perkins, Y. Su, Y. Ma, L. Colson, D. A. Horne, and Y. Chen (2012)
PNAS 109, 4092-4097
   Abstract »    Full Text »    PDF »
A Biochemical Screen for Identification of Small-Molecule Regulators of the Wnt Pathway Using Xenopus Egg Extracts.
C. A. Thorne, B. Lafleur, M. Lewis, A. J. Hanson, K. K. Jernigan, D. C. Weaver, K. A. Huppert, T. W. Chen, C. Wichaidit, C. S. Cselenyi, et al. (2011)
J Biomol Screen 16, 995-1006
   Abstract »    Full Text »    PDF »
An Ultra-High Throughput Cell-Based Screen for Wee1 Degradation Inhibitors.
F. Madoux, S. Simanski, P. Chase, J. K. Mishra, W. R. Roush, N. G. Ayad, and P. Hodder (2010)
J Biomol Screen 15, 907-917
   Abstract »    Full Text »    PDF »
Activation Domain-dependent Degradation of Somatic Wee1 Kinase.
L. Owens, S. Simanski, C. Squire, A. Smith, J. Cartzendafner, V. Cavett, J. Caldwell Busby, T. Sato, and N. G. Ayad (2010)
J. Biol. Chem. 285, 6761-6769
   Abstract »    Full Text »    PDF »
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 »
The ubiquitin-proteasome system regulates membrane fusion of yeast vacuoles.
M. F. Kleijnen, D. S. Kirkpatrick, and S. P. Gygi (2007)
EMBO J. 26, 275-287
   Abstract »    Full Text »    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.
J. S. Stanford and J. V. Ruderman (2005)
Mol. Biol. Cell 16, 5749-5760
   Abstract »    Full Text »    PDF »
Ubiquitin Binding Site of the Ubiquitin E2 Variant (UEV) Protein Mms2 Is Required for DNA Damage Tolerance in the Yeast RAD6 Pathway.
C. Tsui, A. Raguraj, and C. M. Pickart (2005)
J. Biol. Chem. 280, 19829-19835
   Abstract »    Full Text »    PDF »
Genetic and chemical analyses of the action mechanisms of sirtinol in Arabidopsis.
X. Dai, K.-i. Hayashi, H. Nozaki, Y. Cheng, and Y. Zhao (2005)
PNAS 102, 3129-3134
   Abstract »    Full Text »    PDF »
CELL BIOLOGY: Chemical Genetics Hits.
D. S. Bellows and M. Tyers (2004)
Science 306, 67-68
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882