Upregulation of the <i>Saccharomyces cerevisiae</i> efflux pump Tpo1 rescues an Imp2 transcription factor‐deficient mutant from bleomycin toxicity

Berra, Siham; Ayachi, Sami; Ramotar, Dindial

doi:10.1002/em.21865

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…Certain cell membrane proteins, notably the human high affinity l -carnitine transporter, can modulate the accumulation of and subsequently the sensitivity of tumour cells to bleomycin. It was found that overexpression of the yeast polyamine transporter TPO1 increased resistance to bleomycin [ 160 ]. The yeast TPO1 transporter was previously found to be involved in the efflux of polyamines from the cell [ 161 , 162 ].…”

Section: Cellular Transport Of Bleomycinmentioning

confidence: 99%

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

Murray

Chen

Chung

2018

IJMS

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The cancer chemotherapeutic drug, bleomycin, is clinically used to treat several neoplasms including testicular and ovarian cancers. Bleomycin is a metallo-glycopeptide antibiotic that requires a transition metal ion, usually Fe(II), for activity. In this review, the properties of bleomycin are examined, especially the interaction of bleomycin with DNA. A Fe(II)-bleomycin complex is capable of DNA cleavage and this process is thought to be the major determinant for the cytotoxicity of bleomycin. The DNA sequence specificity of bleomycin cleavage is found to at 5′-GT* and 5′-GC* dinucleotides (where * indicates the cleaved nucleotide). Using next-generation DNA sequencing, over 200 million double-strand breaks were analysed, and an expanded bleomycin sequence specificity was found to be 5′-RTGT*AY (where R is G or A and Y is T or C) in cellular DNA and 5′-TGT*AT in purified DNA. The different environment of cellular DNA compared to purified DNA was proposed to be responsible for the difference. A number of bleomycin analogues have been examined and their interaction with DNA is also discussed. In particular, the production of bleomycin analogues via genetic manipulation of the modular non-ribosomal peptide synthetases and polyketide synthases in the bleomycin gene cluster is reviewed. The prospects for the synthesis of bleomycin analogues with increased effectiveness as cancer chemotherapeutic agents is also explored.

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Section: Cellular Transport Of Bleomycinmentioning

confidence: 99%

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

Murray

Chen

Chung

2018

IJMS

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“…The single-copy plasmid pSTE5-GFP carrying the entire STE5 gene under its promoter and tagged with GFP was kindly provided by Dr. Peter M. Pryciak (University of Massachusetts medical school, Worcester, MA, USA). The plasmid pSTE5-Myc was constructed by gap repair using pTW438 as the backbone and as previously decsribed 26 . All chemical reagents including rapamycin, methyl methanesulfonate, 4-nitroquinoline-1-oxide, bleomycin and sodium arsenite were purchased from Sigma, St Louis, USA.…”

Section: Methodsmentioning

confidence: 99%

The histone H2B Arg95 residue links the pheromone response pathway to rapamycin-induced G1 arrest in yeast

Sulaiman

Ali

Aouida

et al. 2022

Sci Rep

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Rapamycin is an immunosuppressant used for treating many types of diseases such as kidney carcinomas. In yeast, rapamycin inhibits the TORC1 kinase signaling pathway causing rapid alteration in gene expression and ultimately cell cycle arrest in G1 through mechanisms that are not fully understood. Herein, we screened a histone mutant collection and report that one of the mutants, H2B R95A, is strikingly resistant to rapamycin due to a defective cell cycle arrest. We show that the H2B R95A causes defects in the expression of a subset of genes of the pheromone pathway required for α factor-induced G1 arrest. The expression of the STE5 gene and its encoded scaffold protein Ste5, required for the sequential activation of the MAPKs of the pheromone pathway, is greatly reduced in the H2B R95A mutant. Similar to the H2B R95A mutant, cells devoid of Ste5 are also resistant to rapamycin. Rapamycin-induced G1 arrest does not involve detectable phosphorylation of the MAPKs, Kss1, and Fus3, as reported for α factor-induced G1 arrest. However, we observed a sharp induction of the G1 cyclin Cln2 (~ 3- to 4-fold) in the ste5Δ mutant within 30 min of exposure to rapamycin. Our data provide a new insight whereby rapamycin signaling via the Torc1 kinase may exploit the pheromone pathway to arrest cells in the G1 phase.

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“…Therefore, our laboratory has dedicated research efforts to the study of the biological role and regulation of drug/xenobiotic pumps of the major facilitator superfamily (MFS) and the ATP-binding cassette (ABC) superfamily, and the link between their physiological role and the MDR/MXR phenomenon in yeast (Sá-Correia et al 2009). The S. cerevisiae plasma membrane drug:H + antiporter (DHA) Tpo1, a MDR/MXR transporter of the MFS, has been found to mediate tolerance of this yeast species to a high number of cytotoxic compounds including the metal ions cadmium and aluminium (Cabrito et al 2009), the antimalarial drugs quinidine and artesunate (Alenquer et al 2006; do Valle Matta et al 2001), the immunosuppressant mycophenolic acid (Desmoucelles et al 2002), the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and barban (Cabrito et al 2009; Teixeira and Sá-Correia 2002), the anticancer agent bleomycin (Berra et al 2014; Hillenmeyer et al 2008), the antifungals nodoconazole and mancozeb (Dias et al 2010; Hillenmeyer et al 2008), the nonsteroidal anti-inflammatory drug diclofenac (Mima et al 2007) and the weak acids acetic, propionic, decanoic and octanoic acids (Borrull et al 2015; Legras et al 2010; Mira et al 2009). The apparent promiscuity of Tpo1 and other yeast MFS-MDR transporters in conferring protection to a wide range of structurally unrelated xenobiotic compounds has been questioning the idea that these transporters contribute to MDR by directly mediating the extrusion of the drugs (Dos Santos et al 2014; Mira et al 2010a; Sá-Correia et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Yeast response and tolerance to benzoic acid involves the Gcn4- and Stp1-regulated multidrug/multixenobiotic resistance transporter Tpo1

Godinho

Mira

Cabrito

et al. 2017

Appl Microbiol Biotechnol

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The action of benzoic acid in the food and beverage industries is compromised by the ability of spoilage yeasts to cope with this food preservative. Benzoic acid occurs naturally in many plants and is an intermediate compound in the biosynthesis of many secondary metabolites. The understanding of the mechanisms underlying the response and resistance to benzoic acid stress in the eukaryotic model yeast is thus crucial to design more suitable strategies to deal with this toxic lipophilic weak acid. In this study, the Saccharomyces cerevisiae multidrug transporter Tpo1 was demonstrated to confer resistance to benzoic acid. TPO1 transcript levels were shown to be up-regulated in yeast cells suddenly exposed to this stress agent. This up-regulation is under the control of the Gcn4 and Stp1 transcription factors, involved in the response to amino acid availability, but not under the regulation of the multidrug resistance transcription factors Pdr1 and Pdr3 that have binding sites in TPO1 promoter region. Benzoic acid stress was further shown to affect the intracellular pool of amino acids and polyamines. The observed decrease in the concentration of these nitrogenous compounds, registered upon benzoic acid stress exposure, was not found to be dependent on Tpo1, although the limitation of yeast cells on nitrogenous compounds was found to activate Tpo1 expression. Altogether, the results described in this study suggest that Tpo1 is one of the key players standing in the crossroad between benzoic acid stress response and tolerance and the control of the intracellular concentration of nitrogenous compounds. Also, results can be useful to guide the design of more efficient preservation strategies and the biotechnological synthesis of benzoic acid or benzoic acid-derived compounds.Electronic supplementary materialThe online version of this article (doi:10.1007/s00253-017-8277-6) contains supplementary material, which is available to authorized users.

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Upregulation of the Saccharomyces cerevisiae efflux pump Tpo1 rescues an Imp2 transcription factor‐deficient mutant from bleomycin toxicity

Cited by 4 publications

References 26 publications

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

The histone H2B Arg95 residue links the pheromone response pathway to rapamycin-induced G1 arrest in yeast

Yeast response and tolerance to benzoic acid involves the Gcn4- and Stp1-regulated multidrug/multixenobiotic resistance transporter Tpo1

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