tailieunhanh - Báo cáo khoa học: The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin

The anticancer agents cisplatin and oxaliplatin are widely used in the treat-ment of human neoplasias. A genome-wide screen inSaccharomyces cere-visiae previously identified PPH3and PSY2among the top 20 genes conferring resistance to these anticancer agents. The mammalian ortho-logue of Pph3p is the protein serine⁄threonine phosphatase Ppp4c, which is found in high molecular mass complexes bound to a regulatory subunit R2. | iFEBS Journal The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin C. James Hastie1 z Cristina V 3zquez-Martin1 z Amanda Philp1 Michael J. R. Stark2 and Patricia T. W. Cohen1 1 MedicalResearch CouncilProtein Phosphorylation Unit Schoolof Life Sciences University of Dundee UK 2 Division of Gene Regulation and Expression Schoolof Life Sciences University of Dundee UK Keywords cisplatin platinum-based anticancer drugs Pph3 protein phosphatase 4 Psy4 Correspondence P. T. W. Cohen MRC Protein Phosphorylation Unit Schoolof Life Sciences MSI WTB CIR University of Dundee Dow Street Dundee DD1 5EH UK Fax 44 1382 223778 Tel. 44 1382 384240 E-mail These authors contributed equally to this work. Received 28 April2006 revised 22 May 2006 accepted 24 May 2006 doi The anticancer agents cisplatin and oxaliplatin are widely used in the treatment of human neoplasias. A genome-wide screen in Saccharomyces cere-visiae 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 .