Document Detail

Role of proteasomal degradation in the cell cycle-dependent regulation of DNA topoisomerase IIalpha expression.
MedLine Citation:
PMID:  11274964     Owner:  NLM     Status:  MEDLINE    
1DNA topoisomerase II (topo II) is a nuclear enzyme that modifies DNA topology and also serves as a target to mediate the cytotoxicity of several antineoplastic agents. Several reports have demonstrated that a reduction of topo II is associated with reduced sensitivity to these agents. Topo II exists as two isoforms in mammalian cells: topo IIalpha and topo IIbeta. In MCF-7 cells, the half-life (mean +/- SEM) values of topo IIalpha and topo IIbeta in situ were 6.6 +/- 0.3 and 17.6 +/- 2.3 hr, respectively, as determined by [(35)S]methionine/cysteine pulse-chase analysis. Degradation of topo IIalpha in situ was abrogated by the presence of proteasome inhibitors, and the relative activities were carbobenzoxy-leucyl-leucyl-leucinal (MG132) > carbobenzoxy-leucyl-leucyl-norvalinal (MG115) > ALLN congruent with lactacystin. ATP-dependent degradation of topo IIalpha, but not topo IIbeta, was observed in extracts of asynchronously dividing HeLa and MCF-7 cells. Furthermore, degradation of topo IIalpha was abrogated by the proteasome inhibitors MG132 and MG115, but not by lactacystin, in extracts of asynchronously dividing MCF-7 cells. Finally, degradation of topo IIalpha, but not topo IIbeta, was observed to occur in a cell cycle-dependent fashion, in extracts of synchronized HeLa cells, with maximal loss of the alpha isoform occurring 2 hr after release from mitotic arrest. This degradation of topo IIalpha appeared to be facilitated by an ATP-dependent activity. Furthermore, high molecular weight bands (>200 kDa), which may represent polyubiquitinated-topo IIalpha conjugates, were also detected in extracts of synchronized HeLa cells. This study provides evidence for a role of the ubiquitin-proteasome pathway in the cell cycle-dependent regulation of topo IIalpha expression.
L Salmena; V Lam; J P McPherson; G J Goldenberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  61     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2001 Apr 
Date Detail:
Created Date:  2001-03-29     Completed Date:  2001-04-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  795-802     Citation Subset:  IM    
Department of Pharmacology, University of Toronto, M5S 3E2, Toronto, Ontario, Canada.
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MeSH Terms
Acetylcysteine / analogs & derivatives*,  pharmacology
Adenosine Triphosphate / metabolism
Antigens, Neoplasm
Cell Cycle / drug effects,  physiology
Cell Extracts
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / pharmacology
DNA Topoisomerases, Type II / biosynthesis,  metabolism*
DNA Topoisomerases, Type II, Eukaryotic*
DNA-Binding Proteins
Hela Cells
Isoenzymes / biosynthesis,  metabolism*
Leupeptins / pharmacology
Multienzyme Complexes / antagonists & inhibitors,  metabolism*
Proteasome Endopeptidase Complex
Tumor Cells, Cultured
Reg. No./Substance:
0/Antigens, Neoplasm; 0/Cell Extracts; 0/Cysteine Proteinase Inhibitors; 0/DNA-Binding Proteins; 0/Isoenzymes; 0/Leupeptins; 0/Multienzyme Complexes; 0/carbobenzoxy-leucyl-leucyl-norvalinal; 110044-82-1/acetylleucyl-leucyl-norleucinal; 133343-34-7/lactacystin; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 56-65-5/Adenosine Triphosphate; 616-91-1/Acetylcysteine; EC 3.4.22.-/Cysteine Endopeptidases; EC Endopeptidase Complex; EC 5.99.1.-/DNA Topoisomerases, Type II, Eukaryotic; EC Topoisomerases, Type II; EC topoisomerase II alpha; EC topoisomerase II beta

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