Tryprostatin A, a specific and novel inhibitor of microtubule assembly

Author:

Takeo USUI, Masuo KONDOH, Cheng-Bin CUI, Tadanori MAYUMI and Hiroyuki OSADA

Date: 6 May 2009

Abstract:

We have investigated the cell cycle inhibition mechanism andprimary target of tryprostatin A (TPS-A) puri®ed fromAspergillus fumigatus. TPS-A inhibited cell cycle progression ofasynchronously cultured 3Y1 cells in the M phase in a dose- andtime-dependent manner. In contrast, TPS-B (the demethoxyanalogue of TPS-A) showed cell-cycle non-speci®c inhibition oncell growth even though it inhibited cell growth at lowerconcentrations than TPS-A. TPS-A treatment induced the reversibledisruption of the cytoplasmic microtubules of 3Y1 cellsas observed by indirect immuno¯uorescence microscopy in therange of concentrations that speci®cally inhibited M-phaseprogression. TPS-A inhibited the assembly in šitro of micro-tubules puri®ed from bovine brains (40%inhibition at 250 lM);however, there was little or no effect on the self-assembly ofpuri®ed tubulin when polymerization was induced by glutamateeven at 250 lM TPS-A. TPS-A did not inhibit assemblypromoted by taxol or by digestion of the C-terminal domain oftubulin. However, TPS-A blocked the tubulin assembly inducedby inducers interacting with the C-terminal domain, microtubuleassociatedprotein 2 (MAP2), tau and poly-(l-lysine). Theseresults indicate that TPS-A is a novel inhibitor of MAPdependentmicrotubule assembly and, through the disruption ofthe microtubule spindle, speci®cally inhibits cell cycle progressionat the M phase.

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