The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin

Abstract

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, pph3Δ, ybl046wΔ and psy2Δ, 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.

Identification of Genes inSaccharomyces cerevisiaethat Are Haploinsufficient for Overcoming Amino Acid Starvation

“…Based on sequence similarities, Psy4 was identified as the yeast ortholog of the mammalian R2 core regulatory subunit of the Ppp4c phosphatase, forming a complex with the regulatory Psy2 and the catalytic Pph3 subunits (Hastie et al 2006). Although these genes have been linked to DNA damage repair (Vazquez-Martin et al 2008), there is evidence that this phosphatase complex regulates the Gln3 transcriptional activator of nitrogen-responsive genes in response to nutrient signaling (Bertram et al 2000).…”

Expression and regulation of type 2A protein phosphatases and alpha4 signalling in cardiac health and hypertrophy

“…Evidence suggests that an active unit of the PP4 phosphatase can be comprised of either a simple heterodimer of PP4C and R1/R2 (low activity) or an active heterotrimer with any two of the aforementioned regulatory subunits [16, 26]. In addition, the R2 subunit is thought to confer cisplatin resistance in mammalian cells [29]. Furthermore, the R3 regulatory subunit can be subdivided into two closely related homologues α and β, of which the R3α isoform is overexpressed in breast and lung cancers [81].…”

The anti-tumor activator sMEK1 and paclitaxel additively decrease expression of HIF-1α and VEGF via mTORC1-S6K/4E-BP-dependent signaling pathways

“…sMEK1 tumor suppressor, termed the protein phosphatase 4 regulatory subunit 3 (PP4R3), is a highly conserved protein phosphatase family of serine/threonine phosphatases associated with sensitivity to traditional anti-cancer drugs [18, 19]. sMEK1 plays an important role in cellular biological functions, such as microtubule organization, apoptosis, cell cycle arrest, growth, DNA damage checkpoint, TNF signaling, and PI3K/Akt signaling [20-22].…”