Enhancing Drug Accumulation in<i>Saccharomyces cerevisiae</i>by Repression of Pleiotropic Drug Resistance Genes with Chimeric Transcription Repressors

Stepanov, Alexander A.; Nitiss, Karin C.; Neale, Geoffrey; Nitiss, John L.

doi:10.1124/mol.107.044651

Cited by 34 publications

(34 citation statements)

References 45 publications

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“…1 and 2 show that KP1019 exerts both cytotoxic and cytostatic effects on yeast. Although the concentration of KP1019 that kills approximately 50% of wild-type yeast (163mg/ml or 273mM) is somewhat higher than the IC 50 values (56-179mM) reported for cancer cells in vitro (Heffeter et al, 2005;Heffeter et al, 2010), this result is not surprising given that yeast often display higher levels of resistance to antineoplastic agents (Stepanov et al, 2008).…”

Section: Discussionmentioning

confidence: 43%

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

et al. 2012

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The anticancer ruthenium complex trans-[tetrachlorobis(1H-indazole)ruthenate(III)], otherwise known as KP1019, has previously been shown to inhibit proliferation of ovarian tumor cells, induce DNA damage and apoptosis in colon carcinoma cells, and reduce tumor size in animal models. Notably, no doselimiting toxicity was observed in a Phase I clinical trial. Despite these successes, KP1019's precise mechanism of action remains poorly understood. To determine whether Saccharomyces cerevisiae might serve as an effective model for characterizing the cellular response to KP1019, we first confirmed that this drug is internalized by yeast and induces mutations, cell cycle delay, and cell death. We next examined KP1019 sensitivity of strains defective in DNA repair, ultimately showing that rad1D, rev3D, and rad52D yeast are hypersensitive to KP1019, suggesting that nucleotide excision repair (NER), translesion synthesis (TLS), and recombination each play a role in drug tolerance. These data are consistent with published work showing that KP1019 causes interstrand cross-links and bulky DNA adducts in mammalian cell lines. Published research also showed that mammalian cell lines resistant to other chemotherapeutic agents exhibit only modest resistance, and sometimes hypersensitivity, to KP1019. Here we report similar findings for S. cerevisiae. Whereas gain-of-function mutations in the transcription activator-encoding gene PDR1 are known to increase expression of drug pumps, causing resistance to structurally diverse toxins, we now demonstrate that KP1019 retains its potency against yeast carrying the hypermorphic alleles PDR1-11 or PDR1-3. Combined, these data suggest that S. cerevisiae could serve as an effective model system for identifying evolutionarily conserved modulators of KP1019 sensitivity.

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Section: Discussionmentioning

confidence: 43%

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

et al. 2012

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“…(F and G)The frequency of dynein localization to either microtubule plus ends, the cell cortex, or spindle pole bodies (SPBs) is plotted for indicated strains and drug treatment (for mitotic cells only). In addition to the indicated alleles and drug treatment, the plot in panel G depicts cells that possess the prd1-DBD-CYC8 allele, which represses transcription of pleiotropic drug resistance genes91 , thus promoting intracellular retention of MG132.These cells were treated with 75 µM MG132 for 1.5 hours prior to imaging (control cells were treated with an equal volume of DMSO). Each data point represents the weighted mean ± weighted standard error (73 to 107 mitotic cells from two independent experiments were analyzed for each strain).…”

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confidence: 99%

Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

Marzo

Griswold

Ruff

et al. 2019

Preprint

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Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These "dyneinopathies" define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To overcome complications associated with studying dynein function in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we have determined the molecular basis for several broad classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we have alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein complexes. In addition to revealing molecular insight into dynein regulation, our data reveal an unexpected correlation between the degree of dynein dysfunction and disease type.3

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“…In contrast, the known in vitro telomerase inhibitor, BIBR1532 (Figures 3A and S2F), had no effect upon the growth of control strains or yeast expressing human telomerase (Figure 2F). Furthermore, in a hyperpermeable strain, pdr1 DBD -cyc8 (Stepanov et al., 2008), BIBR1532 was toxic (Figure S2G).…”

Section: Resultsmentioning

confidence: 99%

A Yeast Chemical Genetic Screen Identifies Inhibitors of Human Telomerase

Wong

Unciti‐Broceta

Spitzer

et al. 2013

Chemistry & Biology

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SummaryTelomerase comprises a reverse transcriptase and an internal RNA template that maintains telomeres in many eukaryotes, and it is a well-validated cancer target. However, there is a dearth of small molecules with efficacy against human telomerase in vivo. We developed a surrogate yeast high-throughput assay to identify human telomerase inhibitors. The reversibility of growth arrest induced by active human telomerase was assessed against a library of 678 compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds identified reproducibly restored growth to strains expressing active human telomerase, and three of these four compounds also specifically inhibited purified human telomerase in vitro. These compounds represent probes for human telomerase function, and potential entry points for development of lead compounds against telomerase-positive cancers.

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Enhancing Drug Accumulation inSaccharomyces cerevisiaeby Repression of Pleiotropic Drug Resistance Genes with Chimeric Transcription Repressors

Cited by 34 publications

References 45 publications

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

A Yeast Chemical Genetic Screen Identifies Inhibitors of Human Telomerase

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