Identification of Saccharomyces cerevisiae Tub1 a-Tubulin as a Potential Target for NKH-7, a Cytotoxic 1-Naphthol Derivative Compound

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In a screening for small-molecule compounds that alleviate the deleterious effects of external CaCl2 on zds1Δ strain yeast, we found 2-((1-(hydroxymethyl) cyclohexyl) methyl) naphthalen-1-ol (NKH-7) to be an active compound. NKH-7 also inhibited cell growth at higher concentrations. To identify its target in growth inhibition, we isolated NKH-7-resistant mutants and selected those mutants that exhibited dominant or semi-dominant resistance specifically to NKH-7. By gene cloning, a TUB1 mutant gene encoding α-tubulin with a Ser248Pro mutation was identified. Deletion of the TUB3 gene, a minor gene encoding α-tubulin, led to supersensitivity to NKH-7. Cellular tubulin-containing arrays as visualized by green fluorescent protein (GFP)-labeled α-tubulin diminished rapidly on exposure to the inhibitor. The mutation was situated proximal to the α-β interface of α-tubulin in microtubule protofilaments, suggesting the possibility that NKH-7 affects the hydrolysis of GTP bound to β-tubulin. A functional connection perhaps exists between the tubulin inhibition and Ca2+-dependent cell-cycle regulation.
社団法人日本農芸化学会の論文
2008-04-23