Identification of thioredoxin reductase 1-regulated genes using small interference RNA and cDNA microarray

Gorreta, Francesco; Runfola, Timothy; VanMeter, Amy J.; Barzaghi, D; Chandhoke, Vikas; Giacco, Luca Del

doi:10.4161/cbt.4.10.1987

Cited by 18 publications

(16 citation statements)

References 33 publications

(42 reference statements)

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“…By contrast, our transcriptome analysis showed that Txnrd2 mRNA was not more abundant in mutant embryos (Table 2,Fig. 5a), and, like in Txnrd1-null yeast [32] and Txnrd1-knock-down HepG2 cells [84], most proliferation markers, including mRNAs encoding histones, DNA polymerases, and others, were similar in mutant and wild-type embryos (Table S2). Further analyses on both alleles will likely be required to resolve the complex physiological roles of Txnrd1 in mouse embryos and why such different phenotypes might be manifested.…”

Section: Phenotypic Differences Between Txnrd1 −/− Mouse Linesmentioning

confidence: 82%

“…Interestingly, the most dramatically overrepresented mRNA in mutant embryos was that encoding the insulin-like growth factor-binding protein, IGFBP1 (Table 1). In a recent study, Goretta et al [84] showed that IGFBP3 is up-regulated in cytokine-induced HepG2 human hepatocarcinoma cell cultures that were treated with siRNA targeted to Txnrd1. Increased IGFBP mRNA levels in Txnrd1-deficient cells may be a feedback response to repress excessive signaling from the phosphotyrosine-dependent IGF receptor.…”

Section: Effects On Signalingmentioning

confidence: 99%

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Effects of thioredoxin reductase-1 deletion on embryogenesis and transcriptome

Bondareva¹,

Capecchi²,

Iverson³

et al. 2007

Free Radical Biology and Medicine

100

112

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Thioredoxin reductases (Txnrd)1 maintain intracellular redox homeostasis in most organisms. Metazoans Txnrds also participate in signal transduction. Mouse embryos homozygous for a targeted null mutation of the txnrd1 gene, encoding the cytosolic thioredoxin reductase, were viable at embryonic day 8.5 (E8.5) but not at E9.5. Histology revealed that txnrd1 −/− cells were capable of proliferation and differentiation; however, mutant embryos were smaller than wild-type littermates and failed to gastrulate. In situ marker gene analyses indicated primitive streak mesoderm did not form. Microarray analyses on E7.5 txnrd −/− and txnrd +/+ littermates showed similar mRNA levels for peroxiredoxins, glutathione reductases, mitochondrial Txnrd2, and most markers of cell proliferation. Conversely, mRNAs encoding sulfiredoxin, IGF-binding protein 1, carbonyl reductase 3, glutamate cysteine ligase, glutathione S-transferases, and metallothioneins were more abundant in mutants. Many gene expression responses mirrored those in thioredoxin reductase 1-null yeast; however mice exhibited a novel response within the peroxiredoxin catalytic cycle. Thus, whereas yeast induce peroxiredoxin mRNAs in response to thioredoxin reductase disruption, mice induced sulfiredoxin mRNA. In summary, Txnrd1 was required for correct patterning of the early embryo and progression to later development. Conserved responses to Txnrd1 disruption likely allowed proliferation and limited differentiation of the mutant embryo cells.

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Section: Phenotypic Differences Between Txnrd1 −/− Mouse Linesmentioning

confidence: 82%

Section: Effects On Signalingmentioning

confidence: 99%

Effects of thioredoxin reductase-1 deletion on embryogenesis and transcriptome

Bondareva¹,

Capecchi²,

Iverson³

et al. 2007

Free Radical Biology and Medicine

100

112

View full text Add to dashboard Cite

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“…As noted previously, thioredoxin reductase-1 is a relatively nonspecific enzyme, and other potential natural substrates have been reported, including lipoic acid, ascorbyl free radicals, and S-nitrosoglutathione (21,42). A recent study using small interfering RNA to knockdown thioredoxin reductase-1 expression and microarray analysis showed surprisingly few changes in gene expression, only 8 of 20,000 genes on the array, possibly because thioredoxin reductase-1 activity was only decreased 43% by the treatment (27). The genes that did change, leukotriene B4 12-hydroxydehydrogenase, ubiquitin D, differentiationenhancing factor, fibronectin 1, apolipoprotein 3, prosaposin, choline/ethanolamine phosphotransferase, and IFN-a-inducible protein, give little clue to the pathways affected by thioredoxin reductase-1.…”

Section: Discussionmentioning

confidence: 99%

“…A thioredoxin reductase-1 knockout is embryonic lethal in mice, and thioredoxin reductase-1 -deficient fibroblasts derived from the thioredoxin reductase-1 (À/À) embryos do not proliferate in vitro (25). Furthermore, cancer cell growth is inhibited by thioredoxin reductase-1 antisense (26), thioredoxin reductase-1 small interfering RNA (27) and by a mutant redox inactive thioredoxin reductase-1 (28). There are reports that levels of thioredoxin reductase-1 are increased by epidermal growth factor (29) and hypoxia (30) in cancer cells, although tumors show only moderately increased levels of thioredoxin reductase-1 (23,30).…”

Section: Introductionmentioning

confidence: 99%

Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase

Powis

Wipf

Lynch

et al. 2006

Molecular Cancer Therapeutics

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The cytosolic thioredoxin redox system composed of thioredoxin-1 and the NADPH-dependent thioredoxin reductase-1 reductase is an important regulator of cell growth and survival. Thioredoxin-1 is overexpressed in many human tumors where it is associated with increased cell proliferation, decreased apoptosis, and decreased patient survival. We hypothesized that thioredoxin reductase-1 provides a target to inhibit the activity of overexpressed thioredoxin-1 for the development of novel anticancer agents. We found that the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 is a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility. We have therefore developed PX-916, a water-soluble prodrug of a palmarumycin CP1 analogue. PX-916 rapidly releases the parent compound at physiologic pH and in plasma but is stable at acid pH, allowing its i.v. administration. PX-916 is a potent inhibitor of purified human thioredoxin reductase-1 and of thioredoxin reductase-1 activity in cells and tumor xenografts when given to mice and inhibits the downstream targets of thioredoxin-1 signaling, hypoxiainducible factor-1A, and vascular endothelial growth factor in tumors. PX-916 showed excellent antitumor activity against several animal tumor models with some cures. Thus, the study shows that water-soluble inhibitors of thioredoxin reductase-1, such as PX-916, can block thioredoxin-1 signaling in tumors producing marked inhibition of tumor growth. [Mol Cancer Ther 2006; 5(3):630 -6]

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“…RNA isolation and Real-time PCR were performed as previously described. 28 Total RNA was isolated from HeLa cells using the acid guanidinium-phenol-chlorogorm method (Trizol, Invitrogen), and cDNAs were synthesized using the PrimeScript TM 1 st Strand cDNA Synthesis Kit (Invitrogen). The relative amount of mRNA was determined using the SYBR ® GREEN PCR Master Mix (AB,Applied Biosystems) with gene-specific primers for CAC1 or β-actin.…”

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confidence: 99%