Tryprostatin A, a specific and novel inhibitor of microtubule assembly.
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 microM); however, there was little or no effect on the self-assembly of purified tubulin when polymerization was induced by glutamate even at 250 microM 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.
Antibiotics Laboratory, The Institute of Physical and Chemical Research (RIKEN), Hirosawa 2-1, Wako, Saitama 351-01, Japan.
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D000818:Animals; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines; D051381:Rats; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D026121:Indole Alkaloids; D007211:Indoles; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D014404:Tubulin; D016875:tau Proteins; C097858:tryprostatin A; C097859:tryprostatin B