Trivalent Arsenic Inhibits the Functions of Chaperonin Complex

Pan, Xuewen; Reissman, Stefanie; Douglas, Nick; Huang, Zhiwei; Yuan, Daniel; Wang, Xiaoling; McCaffery, J. Michael; Frydman, Judith; Boeke, Jef D.

doi:10.1534/genetics.110.117655

Cited by 52 publications

(80 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The most significant changes were observed for carbohydrate metabolism and nucleotide metabolism. Pan et al (27), using a chemogenomic approach in Saccharomyces cerevisiae, found that the folding of actin and tubulin was disrupted upon the addition of arsenic as a result of its binding to the chaperonin complex TRiC (also called "chaperonin containing TCP-1," CCT) (27). Interestingly, several members of human CCT complex are in our list of arsenic-binding proteins (Dataset S1), including CCT7 and CCT8.…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

Zhang

Yang

Ling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

135

101

View full text Add to dashboard Cite

Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies.arsenic trioxide | human proteome microarray | glycolysis | hexokinase-2IA rsenic and its derivatives have been applied as therapy for a variety of diseases for more than 2,200 y (1). To date, the disease most successfully treated with these types of compounds is acute promyelocytic leukemia (APL). Administration of arsenic trioxide (ATO) combined with all-trans retinoic acid has demonstrated a remarkable 5-y overall survival rate of 85-90% as a consequence of the dramatic down-regulation of the key protein driving APL tumorigenicity, promyelocytic leukemia-retinoic acid receptor α (PML-RARα) (2). However, ATO also has been found to be effective against many other hematologic malignancies and solid tumors. For example, together with imatinib it is a promising treatment for chronic myelocytic leukemia (3), and it has been used alone with some success to treat multiple myeloma (4), myelodysplasia syndrome (5), and non-Hodgkin lymphoma (6). ATO also is under clinical investigation as a possible medication for lung cancer, hepatocellular carcinoma, melanoma, renal cell carcinoma, and colorectal cancer (https://www.clinicaltrials.gov/). At the cellular level, ATO has been shown to inhibit significantly the growth of almost all the cell lines (59 of 60) in the US National Cancer Institute anticancer drug screen that spans nine different tumor types (7). Thus ATO is one of the most promising broadly effective medications against cancer.Although its mode of action in APL is well established, the underlying mechanisms by which ATO acts in other types of cancers remain poorly understood. A variety of systematic studies, including studies that provided transcriptomic, chemogenomic, or proteomic characterizations (8, 9), have been performed to gain a better understanding of this broader anticancer activity of ATO. However, these studies examined only the cellular consequences of treatment with ATO without identifying the primary proteins directly bound and modulated by ATO. Knowledge of ATO...

show abstract

Section: Discussionmentioning

confidence: 99%

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

Zhang

Yang

Ling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

135

101

View full text Add to dashboard Cite

show abstract

Section: Qtl Mapping By Linkage Analysismentioning

confidence: 99%

“…For example, the arsenite QTL at chromosome XI 68-82 kb also had a strong linkage signal for heat growth efficiency at chromosome XI 48 kb. This region contains the gene PEX1, which is an AAAperoxin whose deletion allele in the reference background has a fitness effect under both heat stress (Sinha et al 2008) and arsenite (Pan et al 2010).A segregant population allows detection of antagonistic alleles that increase fitness in spite of coming from an unfit strain or vice versa (Rieseberg et al 2003). For example, although the NA strain has superior resistance to heat, we found NA alleles that are detrimental for this phenotype (Table S3).…”

mentioning

confidence: 92%

High-Resolution Mapping of Complex Traits with a Four-Parent Advanced Intercross Yeast Population

et al. 2013

View full text Add to dashboard Cite

A large fraction of human complex trait heritability is due to a high number of variants with small marginal effects and their interactions with genotype and environment. Such alleles are more easily studied in model organisms, where environment, genetic makeup, and allele frequencies can be controlled. Here, we examine the effect of natural genetic variation on heritable traits in a very large pool of baker's yeast from a multiparent 12th generation intercross. We selected four representative founder strains to produce the Saccharomyces Genome Resequencing Project (SGRP)-4X mapping population and sequenced 192 segregants to generate an accurate genetic map. Using these individuals, we mapped 25 loci linked to growth traits under heat stress, arsenite, and paraquat, the majority of which were best explained by a diverging phenotype caused by a single allele in one condition. By sequencing pooled DNA from millions of segregants grown under heat stress, we further identified 34 and 39 regions selected in haploid and diploid pools, respectively, with most of the selection against a single allele. While the most parsimonious model for the majority of loci mapped using either approach was the effect of an allele private to one founder, we could validate examples of pleiotropic effects and complex allelic series at a locus. SGRP-4X is a deeply characterized resource that provides a framework for powerful and high-resolution genetic analysis of yeast phenotypes and serves as a test bed for testing avenues to attack human complex traits.T HE strong tendency for progeny to closely resemble their parents has turned out to be difficult to understand in detail. Nearly all traits, including lifetime risk for many common diseases, have a complex genetic basis that is determined by multiple quantitative trait loci (QTL) (Donnelly 2008;Manolio et al. 2009). The first step toward accurate models of trait variability, and a prerequisite for predicting and modulating them, is characterization of the underlying genetic factors in the context of rest of the genome and their external environment. Research in model systems has led the way in this effort and produced powerful experimental and computational approaches for genetic mapping (Nordborg and Weigel 2008;Flint and Mackay 2009;Mackay et al. 2009).A traditional, well-controlled approach for finding the QTL underlying natural phenotypic variation is to analyze a large number of progenies from two-parent crosses (Brem et al. 2002;Simon et al. 2008). Studies using this design have improved our understanding of complex traits and provided concrete evidence of natural segregating variants ), but have been limited in their scope with regard to the extent of genetic variation between the two parents. Mapping populations of popular model organisms ranging from fruit flies (King et al. 2012) (Churchill et al. 2004;Durrant et al. 2011) to plants (Kover et al. 2009;Gan et al. 2011;Huang et al. 2011) has recently expanded the genetic and phenotypic diversity available to study by ...

show abstract

“…Trivalent arsenic [arsenite, As(OH) 3 or As(III)] has been shown to interact with several native proteins in mammalian cells, such as actin, tubulin and thioredoxin reductase, and the classical view is that enzyme inhibition is due to binding (Aposhian and Aposhian, 2006;Menzel et al, 1999;Zhang et al, 2007). As(III) disrupts the actin and tubulin cytoskeleton in budding yeast Saccharomyces cerevisiae (Pan et al, 2010;Thorsen et al, 2009), but whether this is caused by direct binding to actin and tubulin is not known. S. cerevisiae responds to As(III) exposure by strongly enhancing expression of chaperoneand proteasome-encoding genes; upregulation of proteasomal components is mediated by the transcription factor Rpn4p and cells lacking this factor are As(III) sensitive (Haugen et al, 2004;Thorsen et al, 2007;Thorsen et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast

Jacobson

Navarrete

Sharma

et al. 2012

Journal of Cell Science

132

225

View full text Add to dashboard Cite

SummarySeveral metals and metalloids profoundly affect biological systems, but their impact on the proteome and mechanisms of toxicity are not fully understood. Here, we demonstrate that arsenite causes protein aggregation in Saccharomyces cerevisiae. Various molecular chaperones were found to be associated with arsenite-induced aggregates indicating that this metalloid promotes protein misfolding. Using in vivo and in vitro assays, we show that proteins in the process of synthesis/folding are particularly sensitive to arsenite-induced aggregation, that arsenite interferes with protein folding by acting on unfolded polypeptides, and that arsenite directly inhibits chaperone activity. Thus, folding inhibition contributes to arsenite toxicity in two ways: by aggregate formation and by chaperone inhibition. Importantly, arsenite-induced protein aggregates can act as seeds committing other, labile proteins to misfold and aggregate. Our findings describe a novel mechanism of toxicity that may explain the suggested role of this metalloid in the etiology and pathogenesis of protein folding disorders associated with arsenic poisoning.

show abstract

Trivalent Arsenic Inhibits the Functions of Chaperonin Complex

Cited by 52 publications

References 43 publications

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

High-Resolution Mapping of Complex Traits with a Four-Parent Advanced Intercross Yeast Population

Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast

Contact Info

Product

Resources

About