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Titolo:
(-DISCODERMOLIDE BINDS TO MICROTUBULES IN STOICHIOMETRIC RATIO TO TUBULIN DIMERS, BLOCKS TAXOL BINDING AND RESULTS IN MITOTIC ARREST())
Autore:
HUNG DT; CHEN J; SCHREIBER SL;
Indirizzi:
HARVARD UNIV,HOWARD HUGHES MED INST,12 OXFORD ST CAMBRIDGE MA 02138 HARVARD UNIV,HOWARD HUGHES MED INST CAMBRIDGE MA 02138 HARVARD UNIV,DEPT CHEM & BIOL CHEM CAMBRIDGE MA 02138
Titolo Testata:
Chemistry & biology
fascicolo: 4, volume: 3, anno: 1996,
pagine: 287 - 293
SICI:
1074-5521(1996)3:4<287:(BTMIS>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
MATURATION-PROMOTING FACTOR; CELL-CYCLE; IMMUNOSUPPRESSIVE COMPOUND; MECHANISM; DISCODERMOLIDE; INVITRO;
Keywords:
CELL CYCLE ARREST; DISCODERMOLIDE; MICROTUBULES; MITOTIC SPINDLES; TAXOL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
21
Recensione:
Indirizzi per estratti:
Citazione:
D.T. Hung et al., "(-DISCODERMOLIDE BINDS TO MICROTUBULES IN STOICHIOMETRIC RATIO TO TUBULIN DIMERS, BLOCKS TAXOL BINDING AND RESULTS IN MITOTIC ARREST())", Chemistry & biology, 3(4), 1996, pp. 287-293

Abstract

Background: The marine natural product (+)-discodermolide has potent immunosuppressive activity. It inhibits proliferation of a wide range of human and murine cells, induces cell cycle arrest in the G2 or M phase and was recently shown to stabilize microtubules. Total synthesis of discodermolide has made it possible to generate variants of the compound to study its intracellular function in detail. Results: We have determined that (+)-discodermolide arrests MG63 cells at M phase, and has a stabilizing effect on microtubules. in vitro studies show that discodermolide induces polymerization of purified tubulin in the absence of microtubule-associated proteins, and that it binds to tubulin dimers in microtubules at 1:1 stoichiometry. Discodermolide binds taxol-polymerized microtubules at near stoichiometric level, whereas taxol binds discodermolide-induced microtubules poorly. Competition data show that the binding of microtubules by discodermolide and taxol are mutually exclusive; discodermolide binds with higher affinity than taxol. The results of binding assays carried out in vivo or in cell lysates also suggest that the microtubule network is discodermolide's cellular target. Conclusions: (+)-Discodermolide causes cell cycle arrest at themetaphase-anaphase transition in mitosis, presumably due to its stabilizing effect on microtubules. In vitro, discodermolide polymerizes purified tubulin potently in the absence of MAPs. It binds microtubules at one molecule per tubulin dimer with a higher affinity than taxol, and the binding of microtubules by discodermolide and taxol are mutually exclusive. In total cell lysates discodermolide displays binding activity that is consistent with its effects on microtubules.

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Documento generato il 29/09/20 alle ore 05:29:49