Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export.
Trichostatin A (TSA), an inhibitor of the eukaryotic cell cycle and an inducer of morphological reversion of transformed cells, inhibits histone deacetylase (HDAC) at nanomolar concentrations. Recently, trapoxin, oxamflatin, and FR901228, antitumor agents structurally unrelated to TSA, were found to be potent HDAC inhibitors. These inhibitors activate expression of p21Waf1 and 16INK4A in a p53-independent manner. Changes in the expression of these cell cycle regulators by an increase in histone acetylation may be responsible for cell cycle arrest and antitumor activity by HDAC inhibitors. The target molecule of leptomycin B (LMB), a potent antitumor agent, was genetically and biochemically identified as CRM1, a protein reported as being required for chromosome structure control. We showed that CRM1 was a receptor for the nuclear export signal (NES) and that LMB inhibited nuclear export of proteins. Using LMB, we identified a novel NES in fission yeast transcription factor Pap1, the function of which is abolished by oxidative stress in a manner conserved in eukaryotes.
Yoshida
M
M
Department of Biotechnology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Japan. ayoshida@mail.cc.u-tokyo.ac.jp
Horinouchi
S
S
D000107:Acetylation; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology / Q000627:therapeutic use; D018260:Gelsolin / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D028884:Karyopherins; D000073718:Pancreatitis-Associated Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction; D000097606:Exportin 1 Protein
D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D018260:Gelsolin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D028884:Karyopherins; D000073718:Pancreatitis-Associated Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C000612141:REG3A protein, human; C012589:trichostatin A; C038753:leptomycin B