Peroxiredoxin 2 mediates insulin sensitivity of skeletal muscles through regulation of protein tyrosine phosphatase oxidation

Kim, Jung‐Hak; Park, Sun-Ji; Chae, Unbin; Seong, Joongbae; Lee, Hyun‐Shik; Lee, Sang-Rae; Lee, Seung‐Hoon; Lee, Dong‐Seok

doi:10.1016/j.biocel.2018.03.019

Cited by 15 publications

(14 citation statements)

References 56 publications

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“…As both PRDX1 9 and 2 25 have been previously shown to regulate the prosurvival PI3K/Akt-mediated signalling in a cell type-dependent manner, we assessed the Ser 473 Akt phosphorylation status in MCF-7 cells devoid of either PRDX1 or PRDX2. As shown in Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents

et al. 2018

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Background Our previous work has shown peroxiredoxin-1 (PRDX1), one of major antioxidant enzymes, to be a biomarker in human breast cancer. Hereby, we further investigate the role of PRDX1, compared to its close homolog PRDX2, in mammary malignant cells. Methods CRISPR/Cas9- or RNAi-based methods were used for genetic targeting PRDX1/2. Cell growth was assessed by crystal violet, EdU incorporation or colony formation assays. In vivo growth was assessed by a xenotransplantation model. Adenanthin was used to inhibit the thioredoxin-dependent antioxidant defense system. The prooxidant agents used were hydrogen peroxide, glucose oxidase and sodium L-ascorbate. A PY1 probe or HyPer-3 biosensor were used to detect hydrogen peroxide content in samples. Results PRDX1 downregulation significantly impaired the growth rate of MCF-7 and ZR-75-1 breast cancer cells. Likewise, xenotransplanted PRDX1 - deficient MCF-7 cells presented a retarded tumour growth. Furthermore, genetic targeting of PRDX1 or adenanthin, but not PRDX2, potently sensitised all six cancer cell lines studied, but not the non-cancerous cells, to glucose oxidase and ascorbate. Conclusions Our study pinpoints the dominant role for PRDX1 in management of exogeneous oxidative stress by breast cancer cells and substantiates further exploration of PRDX1 as a target in this disease, especially when combined with prooxidant agents.

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Section: Resultsmentioning

confidence: 99%

Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents

et al. 2018

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“…PRDX2 protects hippocampal neurons from age-dependent mitochondrial decay [72] and maintains the stemness of mouse embryonic stem cells [38]. Oxidation of protein tyrosine phosphatases by ROS in Prdx2 −/− fed a high-fat diet causes reduced body weight and increased glucose clearance [73]. PRDX2 controls corpus luteum regression that is induced by prostaglandin F2α-mediated ROS and protects against age-related ovarian failure [74,75].…”

Section: Othersmentioning

confidence: 99%

Knockout Mouse Models for Peroxiredoxins

Lee

2020

Antioxidants

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Peroxiredoxins (PRDXs) are members of a highly conserved peroxidase family and maintain intracellular reactive oxygen species (ROS) homeostasis. The family members are expressed in most organisms and involved in various biological processes, such as cellular protection against ROS, inflammation, carcinogenesis, atherosclerosis, heart diseases, and metabolism. In mammals, six PRDX members have been identified and are subdivided into three subfamilies: typical 2-Cys (PRDX1, PRDX2, PRDX3, and PRDX4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) subfamilies. Knockout mouse models of PRDXs have been developed to investigate their in vivo roles. This review presents an overview of the knockout mouse models of PRDXs with emphases on the biological and physiological changes of these model mice.

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“…Peroxiredoxins are the preferential targets of H2O2 (53) and peroxiredoxins such as PRDX5 and PRDX6 are known to primarily catalyze the conversion of H2O2 to H2O in the mitochondria (138) or in other compartments such as the cytoplasm (139). In parallel to their antioxidant function, peroxiredoxins mediate signaling events through the reversible oxidation of thiol switch proteins, including phosphorylation events through inhibition of protein tyrosine phosphatase proteins (140)(141)(142). Additionally, other phosphorylation signaling cascades via the apoptosis signaling kinase1 (ASK1) and mitogen activated protein kinase (MAPK) can be modulated by peroxiredoxins (143,144).…”

Section: Fine-tuning Mtros Along Metabolic Reprogramming Of T Cellsmentioning

confidence: 99%

Identification of mtROS-sensitive processes in activated CD4⁺T cells

Meston

Rietschel

et al. 2020

Preprint

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T lymphocytes are key components in adaptive immunity and their activation naturally involves mitochondrial-derived oxygen species (mtROS). In particular, H2O2 has been implicated as an important signaling molecule regulating major T cell functions. H2O2 targets the oxidation status of functional cysteine residues but knowledge if and where this happens in T cell signaling networks is widely missing. This study aimed to identify mtROS-sensitive processes in activated primary human CD4 + T cells. By using a thiolspecific redox proteomic approach we examined the oxidation state of 4784 cysteinecontaining peptides of ex vivo stimulated T cells from healthy individuals. Upon activation, a shift in oxidation was observed at catalytic cysteine residues of peroxiredoxins (PRDX5 & PRDX6), and T cells were found to maintain their global thiol-redox homeostasis. In parallel, a distinct set of 88 cysteine residues were found to be differentially oxidized upon T cell activation suggesting novel functional thiol switches. In mitochondria, cysteine oxidations selectively modified regulators of respiration (NDUFA2, NDUFA8, and UQCRH) confirming electron leakage from electron transport complexes I and III. The majority of oxidations occurred outside mitochondria and enriched sensitive thiols at regulators of cytoskeleton dynamics (e.g. CYFIP2 and ARPC1B) and known immune functions including the non-receptor tyrosine phosphatase PTPN7. Conversely, cysteine reduction occurred predominantly at transcriptional regulators and sites that coordinate zinc-binding in zinc-finger motifs. Indeed, fluorescence microscopy revealed a colocalization of zinc-rich microenvironments and mitochondria in T cells suggesting mtROS-dependent zincrelease of identified transcriptional regulators including ZFP36, RPL37A and CRIP2. In conclusion, this study complements knowledge on the mtROS signaling network and suggests zinc-dependent thiol switches as a mechanism of how mtROS affects transcription and translation in T cells.

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Peroxiredoxin 2 mediates insulin sensitivity of skeletal muscles through regulation of protein tyrosine phosphatase oxidation

Cited by 15 publications

References 56 publications

Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents

Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents

Knockout Mouse Models for Peroxiredoxins

Identification of mtROS-sensitive processes in activated CD4⁺T cells

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Peroxiredoxin 2 mediates insulin sensitivity of skeletal muscles through regulation of protein tyrosine phosphatase oxidation

Cited by 15 publications

References 56 publications

Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents

Targeting peroxiredoxin 1 impairs growth of breast cancer cells and potently sensitises these cells to prooxidant agents

Knockout Mouse Models for Peroxiredoxins

Identification of mtROS-sensitive processes in activated CD4+T cells

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Identification of mtROS-sensitive processes in activated CD4⁺T cells