We have investigated the cell cycle inhibition mechanism and primary target of tryprostatin A (TPS-A) purified from Aspergillus fumigatus. TPS-A inhibited cell cycle progression of asynchronously cultured 3Y1 cells in the M phase in a dose- and time-dependent manner. In contrast, TPS-B (the demethoxy analogue of TPS-A) showed cell-cycle non-specific inhibition on cell growth even though it inhibited cell growth at lower concentrations than TPS-A. TPS-A treatment induced the reversible disruption of the cytoplasmic microtubules of 3Y1 cells as observed by indirect immunofluorescence microscopy in the range of concentrations that specifically inhibited M-phase progression. TPS-A inhibited the assembly in vitro of microtubules purified from bovine brains (40% inhibition at 250 µM); however, there was little or no effect on the self-assembly of purified tubulin when polymerization was induced by glutamate even at 250 µM TPS-A. TPS-A did not inhibit assembly promoted by taxol or by digestion of the C-terminal domain of tubulin. However, TPS-A blocked the tubulin assembly induced by inducers interacting with the C-terminal domain, microtubule-associated protein 2 (MAP2), tau and poly-(l-lysine). These results indicate that TPS-A is a novel inhibitor of MAP-dependent microtubule assembly and, through the disruption of the microtubule spindle, specifically inhibits cell cycle progression at the M phase.
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August 1998
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Research Article|
August 01 1998
Tryprostatin A, a specific and novel inhibitor of microtubule assembly
Takeo USUI;
Takeo USUI
*Antibiotics Laboratory, The Institute of Physical and Chemical Research (RIKEN), Hirosawa 2-1, Wako, Saitama 351-01, Japan
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Masuo KONDOH;
Masuo KONDOH
*Antibiotics Laboratory, The Institute of Physical and Chemical Research (RIKEN), Hirosawa 2-1, Wako, Saitama 351-01, Japan
†Faculty of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565, Japan
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Tadanori MAYUMI;
Tadanori MAYUMI
†Faculty of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565, Japan
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Hiroyuki OSADA
Hiroyuki OSADA
2
*Antibiotics Laboratory, The Institute of Physical and Chemical Research (RIKEN), Hirosawa 2-1, Wako, Saitama 351-01, Japan
2To whom correspondence should be addressed (e-mail antibiot@postman.riken.go.jp).
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Publisher: Portland Press Ltd
Received:
October 20 1997
Revision Received:
April 15 1998
Accepted:
April 22 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 333 (3): 543–548.
Article history
Received:
October 20 1997
Revision Received:
April 15 1998
Accepted:
April 22 1998
Citation
Takeo USUI, Masuo KONDOH, Cheng-Bin CUI, Tadanori MAYUMI, Hiroyuki OSADA; Tryprostatin A, a specific and novel inhibitor of microtubule assembly. Biochem J 1 August 1998; 333 (3): 543–548. doi: https://doi.org/10.1042/bj3330543
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