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Expression of inactive forms of yeast DNA toposiomerase II confers resistance to an anticancer drug, etoposideстатья
Информация о цитировании статьи получена из
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Дата последнего поиска статьи во внешних источниках: 24 мая 2016 г.
- Авторы: VASSETZKY Y.S., Roberts E., Alghisi G.C., Gasser S.M.
- Журнал: British Journal of Cancer
- Том: 73
- Год издания: 1996
- Издательство: Nature Publishing Group
- Местоположение издательства: United Kingdom
- Первая страница: 1201
- Последняя страница: 1209
- DOI: 10.1038/bjc.1996.231
- Аннотация: Drug resistance to anti-tumour agents often coincides with mutations in the gene encoding DNA topoisomerase II alpha. To examine how inactive forms of topoisomerase II can influence resistance to the chemotherapeutic agent VP-16 (etoposide) in the presence of a wild-type allele, we have expressed point mutations and carboxy-terminal truncations of yeast topoisomerase II from a plasmid in budding yeast. Truncations that terminate the coding region of topoisomerase II at amino acid (aa) 750, aa 951 and aa 1044 are localised to both the cytosol and the nucleus and fail to complement a temperature-sensitive top2-1 allele at non-permissive temperature. In contrast, the plasmid-borne wild-type TOP2 allele and a truncation at aa 1236 are nuclear localised and complement the top2-1 mutation. At low levels of expression, truncated forms of topoisomerase II render yeast resistant to levels of etoposide 2- and 3-fold above that tolerated by cells expressing the full-length enzyme. Maximal resistance is conferred by the full-length enzyme carrying a mutated active site (Y783F) or a truncation at aa 1044. The level of phosphorylation of topoisomerase II was previously shown to correlate with drug resistance in cultured cells, hence we tested mutants in the major casein kinase II acceptor sites in the C-terminal domain of yeast topoisomerase II for changes in drug sensitivity. Neither ectopic expression of the C-terminal domain alone nor phosphoacceptor site mutants significantly alter the host cell's sensitivity to etoposide.
- Добавил в систему: Васецкий Егор Сергеевич