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J. Biol. Chem., Vol. 265, Issue 28, 17174-17179, 10, 1990
M Yoshida, M Kijima, M Akita and T Beppu
(R)-Trichostatin A (TSA) is a Streptomyces product which causes the
induction of Friend cell differentiation and specific inhibition of the
cell cycle of normal rat fibroblasts in the G1 and G2 phases at the very
low concentrations. We found that TSA caused an accumulation of acetylated
histone species in a variety of mammalian cell lines. Pulse- labeling
experiments indicated that TSA markedly prolonged the in vivo half-life of
the labile acetyl groups on histones in mouse mammary gland tumor cells,
FM3A. The partially purified histone deacetylase from wild-type FM3A cells
was effectively inhibited by TSA in a noncompetitive manner with Ki = 3.4
nM. A newly isolated mutant cell line of FM3A resistant to TSA did not show
the accumulation of the acetylated histones in the presence of a higher
concentration of TSA. The histone deacetylase preparation from the mutant
showed decreased sensitivity to TSA (Ki = 31 nM, noncompetitive). These
results clearly indicate that TSA is a potent and specific inhibitor of the
histone deacetylase and that the in vivo effect of TSA on cell
proliferation and differentiation can be attributed to the inhibition of
the enzyme.
Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A
Department of Agricultural Chemistry, Faculty of Agriculture, University of Tokyo, Japan.
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