Document Detail


Mechanism of topoisomerase II inhibition by staurosporine and other protein kinase inhibitors.
MedLine Citation:
PMID:  8824299     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Topoisomerase II is an essential enzyme for proliferation of eukaryotic cells. It is also a target for many antineoplastic drugs that promote stabilization of covalent complexes between topoisomerase II and DNA. Topoisomerase II and protein kinases both catalyze the transfer of phosphoester bonds from nucleotides to proteins. This similarity suggests that inhibitors may affect both classes of enzymes. In the present study, we have examined the mechanism of topoisomerase II inhibition by three different classes of protein kinase inhibitors. We report that staurosporine inhibited the catalytic activity of topoisomerase II by blocking the transfer of phosphodiester bonds from DNA to the active tyrosine site, a mechanism of inhibition not previously reported for this enzyme. In contrast, other kinase inhibitors, such as methyl 2,5-dihydroxycinnamate, most likely inactivated topoisomerase II by alkylation of essential amino acids, whereas the mechanism of inhibition of bis-indolylmaleimide possibly involved a direct interaction with DNA.
Authors:
P Lassota; G Singh; R Kramer
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  271     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1996 Oct 
Date Detail:
Created Date:  1996-11-26     Completed Date:  1996-11-26     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  26418-23     Citation Subset:  IM    
Affiliation:
Oncology and Immunology Research Division, Wyeth-Ayerst Research, Pearl River, New York 10965, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Adenylyl Imidodiphosphate / pharmacology
Animals
Cinnamates / pharmacology
Crithidia fasciculata
DNA / metabolism
DNA Topoisomerases, Type II / antagonists & inhibitors*
Enzyme Inhibitors / pharmacology*
Etoposide / pharmacology
Indoles / pharmacology
Maleimides / pharmacology
Piperazines / pharmacology
Protein Kinase Inhibitors*
Staurosporine / pharmacology*
Chemical
Reg. No./Substance:
0/Cinnamates; 0/Enzyme Inhibitors; 0/Indoles; 0/Maleimides; 0/Piperazines; 0/Protein Kinase Inhibitors; 119139-23-0/bisindolylmaleimide; 21416-68-2/ICRF 193; 25612-73-1/Adenylyl Imidodiphosphate; 33419-42-0/Etoposide; 56-65-5/Adenosine Triphosphate; 62996-74-1/Staurosporine; 63177-57-1/methyl 2,5-dihydroxycinnamate; 9007-49-2/DNA; EC 5.99.1.3/DNA Topoisomerases, Type II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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