Publication Date:
2004-10-02
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Verma, Rati -- Peters, Noel R -- D'Onofrio, Mariapina -- Tochtrop, Gregory P -- Sakamoto, Kathleen M -- Varadan, Ranjani -- Zhang, Mingsheng -- Coffino, Philip -- Fushman, David -- Deshaies, Raymond J -- King, Randall W -- CA78048/CA/NCI NIH HHS/ -- GM068276/GM/NIGMS NIH HHS/ -- GM65334/GM/NIGMS NIH HHS/ -- GM66492/GM/NIGMS NIH HHS/ -- P50 CA92131/CA/NCI NIH HHS/ -- R01 GM-45335/GM/NIGMS NIH HHS/ -- R21CA108545/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2004 Oct 1;306(5693):117-20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Howard Hughes Medical Institute (HHMI), California Institute of Technology, Pasadena, CA 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15459393" target="_blank"〉PubMed〈/a〉
Keywords:
Anaphase-Promoting Complex-Cyclosome
;
Animals
;
Cell Extracts
;
Cyclin B/metabolism
;
Cyclin-Dependent Kinase Inhibitor Proteins
;
Cysteine Endopeptidases/metabolism
;
*Drug Evaluation, Preclinical
;
Interphase
;
Mitosis
;
Molecular Structure
;
Multienzyme Complexes/*antagonists & inhibitors/metabolism
;
Ornithine Decarboxylase/metabolism
;
Proteasome Endopeptidase Complex
;
Protein Binding
;
Proteins/*metabolism
;
Quinolines/*metabolism/pharmacology
;
Recombinant Fusion Proteins
;
Saccharomyces cerevisiae Proteins/metabolism
;
Sulfanilic Acids/*metabolism/pharmacology
;
Ubiquitin/*metabolism
;
Ubiquitin-Protein Ligase Complexes/metabolism
;
Xenopus laevis
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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