Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer

Turner-Ivey, Brittany; Manevich, Yefim; Schulte, Jennifer; Kistner-Griffin, Emily; Jezierska‐Drutel, Agnieszka; Liu, Yusen; Neumann, Carola A.

doi:10.1038/onc.2012.624

Cited by 75 publications

(70 citation statements)

References 50 publications

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“…There are several instances where binding of Prxs to target proteins requires oxidation and formation of higher order structures. For example, interactions of Prx1 with components of phosphorylation pathways have been seen in association with H 2 O 2 -mediated cell senescence [40] and p53-mediated cell death after treatment with anti-cancer drugs [41]. Hyperoxidized Prx2 in its high-molecular-mass structure was also found to interact noncovalently with the protein disulfide isomerase ERp46 [42].…”

Section: Discussionmentioning

confidence: 99%

Kinetic analysis of structural influences on the susceptibility of peroxiredoxins 2 and 3 to hyperoxidation

Poynton

Peskin

Haynes

et al. 2016

Biochemical Journal

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Mammalian 2-cysteine peroxiredoxins (Prxs) are susceptible to hyperoxidation by excess H2O2. The cytoplasmic family member Prx2 hyperoxidizes more readily than mitochondrial Prx3 due to slower dimerization of the sulfenic acid (SpOH) intermediate. Four variant amino acids near the C-terminus have been shown to contribute to this difference. We have performed kinetic analysis of the relationship between hyperoxidation and disulfide formation, using whole-protein MS and comparing wild-type (WT) Prx2 and Prx3 with tail-swap mutants in which the four amino acids were reversed. These changes make Prx3 more sensitive and Prx2 less sensitive to hyperoxidation and accounted for ~70% of the difference between the two proteins. The tail swap mutant of Prx3 was also more susceptible when expressed in the mitochondria of HeLa cells. The hyperoxidized product at lower excesses of H2O2 was a semi-hyperoxidized dimer with one active site disulfide and the other a sulfinic acid. For Prx2, increasing the H2O2 concentration resulted in complete hyperoxidation. In contrast, only approximately half the Prx3 active sites underwent hyperoxidation and, even with high H2O2, the predominant product was the hyperoxidized dimer. Size exclusion chromatography (SEC) showed that the oligomeric forms of all redox states of Prx3 dissociated more readily into dimeric units than their Prx2 counterparts. Notably the species with one disulfide and one hyperoxidized active site was decameric for Prx2 and dimeric for Prx3. Reduction and re-oxidation of the hyperoxidized dimer of Prx3 produced hyperoxidized monomers, implying dissociation and rearrangement of the subunits of the functional homodimer.

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Section: Discussionmentioning

confidence: 99%

Kinetic analysis of structural influences on the susceptibility of peroxiredoxins 2 and 3 to hyperoxidation

Poynton

Peskin

Haynes

et al. 2016

Biochemical Journal

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“…Other miR‐494‐targets include mitotic checkpoint genes, such as BUB3 and MAD1 mitotic arrest deficientlike 1 (MAD1L1), which have been identified as causative agents of early aging (29, 35). Furthermore, proteins with known antioxidant activity, such as Mn‐SOD (31), PRDX1, and PRDX6, have been related to cellular senescence (32). Intriguingly, we previously reported that miR‐494 transfection caused ROS accumulation, parallel to induction of senescence (12).…”

Section: Discussionmentioning

confidence: 99%

Identification of miR‐494 direct targets involved in senescence of human diploid fibroblasts

Comegna¹,

Succoio²,

Napolitano

et al. 2014

FASEB j.

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Cellular senescence is a permanent cell cycle arrest triggered by different stimuli. We recently identified up-regulation of microRNA (miR)-494 as a component of the genetic program leading to senescence of human diploid IMR90 fibroblasts. Here, we used 2-dimensional differential gel electrophoresis (2D-DIGE) coupled to mass spectrometry to profile protein expression changes induced by adoptive overexpression of miR-494 in IMR90 cells. miR-494 induced robust perturbation of the IMR90 proteome by significantly (P≤0.05) down-regulating a number of proteins. Combination of mass spectrometry-based identification of down-regulated proteins and bioinformatic prediction of the miR-494 binding sites on the relevant mRNAs identified 26 potential targets of miR-494. Among them, computational analysis identified 7 potential evolution-conserved miR-494 targets. Functional miR-494 binding sites were confirmed in 3'-untranslated regions (UTRs) of 4 of them [heterogeneous nuclear ribonucleoprotein A3 (hnRNPA3), protein disulfide isomerase A3 (PDIA3), UV excision repair protein RAD23 homolog B (RAD23B), and synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP)/heterogeneous nuclear ribonucleoprotein Q (hnRNPQ)]. Their reduced expression correlated with miR-494 up-regulation in senescent cells. RNA interference-mediated knockdown of hnRNPA3 and, to a lesser extent, RAD23B mirrored the senescent phenotype induced by miR-494 overexpression, blunting cell proliferation and causing up-regulation of SA-β-galactosidase and DNA damage. Ectopic expression of hnRNPA3 or RAD23B slowed the appearance of the senescent phenotype induced by miR-494. Overall, these findings identify novel miR-494 direct targets that are involved in cellular senescence.

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“…Prx1 is the most abundant and ubiquitously distributed member of the mammalian Prx family. It has been implicated in regulating cell proliferation, differentiation and apoptosis (31,32). ASK1 interacts with Prx1 in the presence of H 2 O 2 -induced stress and is negatively regulated by Prx1 (23).…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin 1 has an anti-apoptotic role via apoptosis signal-regulating kinase 1 and p38 activation in mouse models with oral precancerous lesions

et al. 2016

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Abstract. Peroxiredoxin 1 (Prx1) is important in the protection of cells from oxidative damage and the regulation of cell proliferation and apoptosis. Prx1 is overexpressed in oral precancerous lesions of oral leukoplakia (OLK) and oral cancer; however, the association between Prx1 expression and OLK pathogenesis remains unknown. The present study investigated the role of Prx1 and its molecular mechanisms in oxidative stress-induced apoptosis during the pathogenesis of OLK. Wild-type and Prx1 knockout mice were treated with 50 µg/ml 4-nitroquinoline-1-oxide (4NQO) or 4NQO + H 2 O 2 for 16 weeks to establish mouse models with tongue precancerous lesions. Apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The expression of Prx1, apoptosis signal-regulating kinase 1 (ASK1), phosphor-ASK1, p38 and phosphor-p38 was analyzed using immunohistochemical staining, and their mRNA expression levels were evaluated by reverse transcription quantitative polymerase chain reaction. The present results demonstrated that 4NQO or 4NQO + H 2 O 2 induced the development of tongue precancerous lesions in Prx1 knockout and wild-type mice. Prx1 was overexpressed in tongue precancerous lesions compared with normal tongue mucosa. There was a significant decrease in the degree of moderate or severe epithelial dysplasia, and mild epithelial dysplasia was clearly elevated, in Prx1 knockout mice treated with 4NQO + H 2 O 2 compared with wild-type mice treated with 4NQO + H 2 O 2 . Prx1 suppressed apoptosis and upregulated phosphor-ASK1 and phosphor-p38 expression in tongue precancerous lesions. The present results suggest that Prx1 suppresses oxidative stress-induced apoptosis via the ASK1/p38 signalling pathway in mouse tongue precancerous lesions. In conclusion, Prx1 and H 2 O 2 have a coordination role in promoting the progression of tongue precancerous mucosa lesions. The present findings provide novel insight into Prx1 function and the mechanisms of Prx1 in OLK pathogenesis.

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Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer

Cited by 75 publications

References 50 publications

Kinetic analysis of structural influences on the susceptibility of peroxiredoxins 2 and 3 to hyperoxidation

Kinetic analysis of structural influences on the susceptibility of peroxiredoxins 2 and 3 to hyperoxidation

Identification of miR‐494 direct targets involved in senescence of human diploid fibroblasts

Peroxiredoxin 1 has an anti-apoptotic role via apoptosis signal-regulating kinase 1 and p38 activation in mouse models with oral precancerous lesions

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