The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin
The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin
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DOI：
10.1111/j.1742-4658.2006.05336.x
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发表时间：
2006-07-01
期刊：
影响因子：
5.4
通讯作者：
Cohen, Patricia T. W.
中科院分区：
文献类型：
--
作者：
Hastie, C. James;Vazquez-Martin, Cristina;Cohen, Patricia T. W.
抗癌药物顺铂和奥沙利铂广泛应用于人类肿瘤的治疗。此前在酿酒酵母中进行的全基因组筛选发现，PPH3和PSY2是对这些抗癌药物具有耐药性的前20个基因之一。Pph3p的哺乳动物同源物是蛋白丝氨酸/苏氨酸磷酸酶Ppp4c，它存在于与调控亚基R2结合的高分子质量复合物中。我们在这里表明，假定的酿酒葡萄球菌R2同源物，由ORF YBL046w编码，与Pph3p结合，并表现出与哺乳动物R2相同的异常高的不对称性。尽管Ppp4c-R2在高等真核生物中心体的微管相关过程中具有重要功能，但纯合缺失YBL046w和两个或一个功能拷贝TUB2基因的酿酒葡萄球菌二倍体菌株存活，并且对微管解聚药物的敏感性并不比对照菌株高。YBL046w编码的蛋白主要表现为核定位。这些研究表明Ppp4c-R2的中心体功能在酵母中不是必需的，或者可能由不同的磷酸酶来完成。酿酒葡萄球菌纯合子二倍体缺失菌株pph3 Delta、ybl046w Delta和psy2 Delta对顺铂的敏感性均高于对照菌株。因此，YBL046w基因赋予顺铂耐药性，并被命名为PSY4（铂敏感性4）。Ppp4c， R2和假定的Psy2p同源物（称为R3）在果蝇和哺乳动物细胞中形成复合体。与酵母系统相比，该复合体可能赋予高等真核生物对顺铂的抗性。
The anticancer agents cisplatin and oxaliplatin are widely used in the treatment of human neoplasias. A genome-wide screen in Saccharomyces cerevisiae previously identified PPH3 and PSY2 among the top 20 genes conferring resistance to these anticancer agents. The mammalian orthologue of Pph3p is the protein serine/threonine phosphatase Ppp4c, which is found in high molecular mass complexes bound to a regulatory subunit R2. We show here that the putative S. cerevisiae orthologue of R2, which is encoded by ORF YBL046w, binds to Pph3p and exhibits the same unusually high asymmetry as mammalian R2. Despite the essential function of Ppp4c-R2 in microtubule-related processes at centrosomes in higher eukaryotes, S. cerevisiae diploid strains with homozygous deletion of YBL046w and two or one functional copies of the TUB2 gene were viable and no more sensitive to microtubule-depolymerizing drugs than the control strain. The protein encoded by YBL046w exhibited a predominantly nuclear localization. These studies suggest that the centrosomal function of Ppp4c-R2 is not required or may be performed by a different phosphatase in yeast. Homozygous diploid deletion strains of S. cerevisiae, pph3 Delta, ybl046w Delta and psy2 Delta, were all more sensitive to cisplatin than the control strain. The YBL046w gene therefore confers resistance to cisplatin and was termed PSY4 (platinum sensitivity 4). Ppp4c, R2 and the putative orthologue of Psy2p (termed R3) are shown here to form a complex in Drosophila melanogaster and mammalian cells. By comparison with the yeast system, this complex may confer resistance to cisplatin in higher eukaryotes.