Statistical issues with microarrays: processing and analysis

Nadon, Robert; Shoemaker, Jennifer

doi:10.1016/s0168-9525(02)02665-3

Cited by 271 publications

(177 citation statements)

References 48 publications

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“…The filtered values used for further analysis are available as supplementary file. Cluster analysis (Eisen et al, 1998;Nadon and Shoemaker, 2002; http:// rana.stanford.edu/software) was performed using the cluster3 and visualized with TreeView (Saldanha, 2004 …”

Section: Rna and Dna Methodsmentioning

confidence: 99%

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

MBoC

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The conserved Target Of Rapamycin (TOR) growth control signaling pathway is a major regulator of genes required for protein synthesis. The ubiquitous toxic metalloid arsenic, as well as mercury and nickel, are shown here to efficiently inhibit the rapamycin-sensitive TORC1 (TOR complex 1) protein kinase. This rapid inhibition of the TORC1 kinase is demonstrated in vivo by the dephosphorylation and inactivation of its downstream effector, the yeast S6 kinase homolog Sch9. Arsenic, mercury, and nickel cause reduction of transcription of ribosome biogenesis genes, which are under the control of Sfp1, a TORC1-regulated transcriptional activator. We report that arsenic stress deactivates Sfp1 as it becomes dephosphorylated, dissociates from chromatin, and exits the nucleus. Curiously, whereas loss of SFP1 function leads to increased arsenic resistance, absence of TOR1 or SCH9 has the opposite effect suggesting that TORC1 has a role beyond down-regulation of Sfp1. Indeed, we show that arsenic activates the transcription factors Msn2 and Msn4 both of which are targets of TORC1 and protein kinase A (PKA). In contrast to TORC1, PKA activity is not repressed during acute arsenic stress. A normal level of PKA activity might serve to dampen the stress response since hyperactive Msn2 will decrease arsenic tolerance. Thus arsenic toxicity in yeast might be determined by the balance between chronic activation of general stress factors in combination with lowered TORC1 kinase activity. INTRODUCTIONThe transition metal arsenic has a long history of human exploitation as both a poison and a medicine. In more recent times EhrlichЈs discovery of the antisyphilitic drug arsphenamine (also known as salvarsan) by systematic chemical modification of arsenic derivatives marked the beginning of modern pharmaceutical research. Arsenic trioxide (ATO) is used today in cancer treatment (Evens et al., 2004;Lu et al., 2007;Wang and Chen, 2008).Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al., 2004;Jin, 2008;Thorsen et al., 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment. These involve reduction of influx through the aquaglyceroporin Fps1p Thorsen et al., 2006); sequestration into the vacuole in the form of glutathione conjugates, metallothionein, and other metal/protein complexes; and active extrusion (Ghosh et al., 1999). In yeast, genome-wide analysis of the transcription patterns in response to arsenic revealed a complex network of transcription factors controlling the expression of several hundred genes (Haugen et al., 2004;Wysocki et al., 2004;Thorsen et al., 2007). Mitogen-activated protein kinases mediate protective responses involving AP-1-and AP-1-like transcription factors in higher eukaryotes and in fungi (Cavigelli et al., 1996;Rodriguez-Gabriel and Russell, 2005;Thorsen et al., 2006).The mechanisms by which arsenic might influence signalin...

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Section: Rna and Dna Methodsmentioning

confidence: 99%

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

MBoC

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“…Transformation reduces the positive correlation between error variance and magnitude of luminosity ratios (Nadon & Shoemaker, 2002). Significant effects of a deficiency on MnSOD will produce luminosity ratios that exceed those expected by chance when the distribution of ratios only reflects environmental and error variance (the null distribution).…”

Section: Discussionmentioning

confidence: 99%

Genomic regions responsible for manganese superoxide dismutase regulation in Drosophila melanogaster

Paul

Duttaroy

2003

Aging Cell

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“…The simplest approach to detecting differential expression is to consider a statistic t that expresses the difference between the observed average expression levels or ratios across the two groups divided by the estimated standard deviation over these groups. This approach can be extended in many ways as witnessed by the recent flurry of publications on the detection of differential expression [60]. We mention only a few possibilities, such as the nonparametric approach in significance analysis of microarrays [61], Bayesian tests [62] or analysis of variance (ANOVA) [63,64].…”

Section: Box 4 Detecting Differential Expressionmentioning

confidence: 99%

Comparison and meta-analysis of microarray data: from the bench to the computer desk

et al. 2003

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Statistical issues with microarrays: processing and analysis

Cited by 271 publications

References 48 publications

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Genomic regions responsible for manganese superoxide dismutase regulation in Drosophila melanogaster

Comparison and meta-analysis of microarray data: from the bench to the computer desk

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