期刊
FEMS YEAST RESEARCH
卷 20, 期 4, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/femsyr/foaa026
关键词
pinostrobin; Saccharomyces cerevisiae; Ca2+-signaling; G(2) cell-cycle regulation; Wee1; Swe1
资金
- Ratchadaphiseksomphot Endowment Fund of Chulalongkorn University [RES560530247-AS]
- 90th Anniversary of Chulalongkorn University Scholarship
- Chulalongkorn University grant
Pinostrobin, a flavonoid compound known for its diverse pharmacological actions, including anti-leukemic and anti-inflammatory activities, has been repeatedly isolated by various screenings, but its action mechanism is still obscure. Previously, pinostrobin was rediscovered in our laboratory using a yeast-based assay procedure devised specifically for the inhibitory effect on the activated Ca2+ signaling that leads the cells to severe growth retardation in the G(2) phase. Here, we attempted to identify target of pinostrobin employing the genetic techniques available in the yeast. Using various genetically engineered yeast strains in which the Ca2+-signaling cascade can be activated by the controlled expression of the various signaling molecules of the cascade, its target was narrowed down to Swe1, the cell-cycle regulatory protein kinase. The Swe1 kinase is situated at the downstream of the Ca2+-signaling cascade and downregulates the Cdc28/Clb complex by phosphorylating the Cdc28 moiety of the complex in the G(2) phase. We further demonstrated that pinostrobin inhibits the protein kinase activity of Swe1 in vivo as estimated by the decreased level of Cdc28 phosphorylation at Tyr-19. Since the yeast SWE1 gene is an ortholog for the human WEE1 gene, our finding implied a potentiality of pinostrobin as the G(2) checkpoint abrogator in cancer chemotherapy.
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