Grx5 Glutaredoxin Plays a Central Role in Protection against Protein Oxidative Damage in <i>Saccharomyces cerevisiae</i>

Rodríguez-Manzaneque, María Teresa; Ros, Joaquim; Cabiscol, Elisa; Sorribas, Albert; Herrero, Enrique

doi:10.1128/mcb.19.12.8180

Cited by 278 publications

(283 citation statements)

References 54 publications

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“…Furthermore, 56MESS down-regulated the transcription factor Met28p, a component of the Cbf1p-Met4p-Met28p complex which participates in the regulation of sulfur metabolism [46]. 56MESS also suppressed the expression of the following genes: PCL5, TPS2, GRX4, XBP1, MNN4 and CCP1, which were shown to be involved in stress response processes [12,51,56,63]. Also downregulated were cellular respiration genes (CYC7, SDH1, SDH2 and NDI1), implicating the involvement of mitochondria in 56MESS cytotoxicity.…”

Section: Cytotoxicity Of 56mess In the Cisplatin-resistant L1210cisr mentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Section: Cytotoxicity Of 56mess In the Cisplatin-resistant L1210cisr mentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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“…Duplicate gels were run for each sample, one for protein staining with SYPRO Ruby prior to protein spot excision, and one for transfer to a polyvinylidene difluoride membrane for immunoblot analysis. Carbonylated proteins were visualized by autoradiography following immunoreaction with anti-dinitrophenyl-horse radish peroxidase antiserum (Dako, Carpinteria, CA) [22] and a Super Signal West Fempto Maximum Sensitivity Kit (Pierce Biotechnology, Inc., Rockford, IL).…”

Section: Detection Of Carbonylated Proteinsmentioning

confidence: 99%

Changes in disulfide bond content of proteins in a yeast strain lacking major sources of NADPH

Minard

Carroll

Weintraub

et al. 2007

Free Radical Biology and Medicine

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A yeast mutant lacking the two major cytosolic sources of NADPH, glucose-6-phosphate dehydrogenase (Zwf1p) and NADP + -specific isocitrate dehydrogenase (Idp2p), has been demonstrated to lose viability when shifted to medium with acetate or oleate as the carbon source. This loss in viability was found to correlate with an accumulation of endogenous oxidative byproducts of respiration and peroxisomal β-oxidation. To assess effects on cellular protein of endogenous versus exogenous oxidative stress, a proteomics approach was used to compare disulfide bondcontaining proteins in the idp2Δzwf1Δ strain following shifts to acetate and oleate media with those in the parental strain following similar shifts to media containing hydrogen peroxide. Among prominent disulfide bond-containing proteins were several with known antioxidant functions. These and several other proteins were detected as multiple electrophoretic isoforms, with some isoforms containing disulfide bonds under all conditions and other isoforms exhibiting a redox-sensitive content of disulfide bonds, i.e., in the idp2Δzwf1Δ strain and in the hydrogen peroxide-challenged parental strain. The disulfide bond content of some isoforms of these proteins was also elevated in the parental strain grown on glucose, possibly suggesting a redirection of NADPH reducing equivalents to support rapid growth. Further examination of protein carbonylation in the idp2Δzwf1Δ strain shifted to oleate medium also led to identification of common and unique protein targets of endogenous oxidative stress.

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“…Cell extracts were obtained as described by Rodriguez-Manzaneque et al (1999), separated in SDS-polyacrylamide gels and transferred to PVDF membranes. The following antibodies were used: anti-Adh (1 : 400 000 dilution; Chemicon), antiaconitase (1 : 2000 dilution; a gift from R. Lill, Philipps-Universität Marburg), anti-a-ketoglutarate dehydrogenase [1 : 5000 dilution; This study…”

Section: Methodsmentioning

confidence: 99%

Chronological and replicative life-span extension in Saccharomyces cerevisiae by increased dosage of alcohol dehydrogenase 1

et al. 2007

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Alcohol dehydrogenase 1 (Adh1)p catalyses the conversion of acetaldehyde to ethanol, regenerating NAD + . In Saccharomyces cerevisiae, Adh1p is oxidatively modified during ageing and, consequently, its activity becomes reduced. To analyse whether maintaining this activity is advantageous for the cell, a yeast strain with an extra copy of the ADH1 gene (2¾ADH1) was constructed, and the effects on chronological and replicative ageing were analysed. The strain showed increased survival in stationary phase (chronological ageing) due to induction of antioxidant enzymes such as catalase and superoxide dismutases. In addition, 2¾ADH1 cells displayed an increased activity of silent information regulator 2 (Sir2)p, an NAD + -dependent histone deacetylase, due to a higher NAD + /NADH ratio. As a consequence, a 30 % extension in replicative life span was observed. Taken together, these results suggest that the maintenance of enzymes that participate in NAD + /NADH balancing is important to chronological and replicative life-span parameters. INTRODUCTIONOne of the features of ageing in Saccharomyces cerevisiae, as well as in other organisms, is the oxidative modification of specific protein targets, whose functions are impaired by such modification. A mild oxidation contributes to marking the protein for degradation (Stadtman & Oliver, 1991), while strong oxidation can promote protein aggregation, making proteins unavailable for proteasome degradation (Grune et al., 2004). The accumulation of these modified proteins in a cell contributes to the ageing phenotype (Harman, 1981;Stadtman, 1992;Stadtman & Levine, 2000;Levine, 2002; Nyström, 2005). In yeasts, replicative ageing refers to the number of cell divisions occurring in a mother yeast cell . Chronological ageing refers to the ability of cells to maintain viability in stationary phase (Herman, 2002).During the last decade investigations of ageing have uncovered physiological and molecular mechanisms involved in this process, as well as providing some clues towards understanding life-span lengthening (Bordone & Guarente, 2005). Calorie restriction is one of the mechanisms that has been consistently proven to extend life span in organisms ranging from yeasts to mammals (Sohal & Weindruch, 1996). In yeast, the replicative life span can be increased by shifting the cells from 2 to 0.5 % glucose (calorie restriction) (Lin et al., , 2004. One of the key molecules is the silent information regulator 2 (Sir2)p, a class III NAD + -dependent histone deacetylase, which is involved in several physiologically important functions such as silencing telomeres and rDNA, maintaining genome integrity, and ageing (Bitterman et al., 2003). Strains that have an extra copy of the SIR2 gene have a life span extended by 40 %, while deletion of SIR2 shortens life span by 50 % (Kaeberlein et al., 1999). Under calorie restriction, the oxygen consumption increases, thus raising the NAD + /NADH ratio by lowering the concentration of NADH. Since NADH has been described as a Sir2p inhibitor, calorie res...

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Grx5 Glutaredoxin Plays a Central Role in Protection against Protein Oxidative Damage in Saccharomyces cerevisiae

Cited by 278 publications

References 54 publications

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Changes in disulfide bond content of proteins in a yeast strain lacking major sources of NADPH

Chronological and replicative life-span extension in Saccharomyces cerevisiae by increased dosage of alcohol dehydrogenase 1

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