Regulation of Reactive Oxygen Species Homeostasis by Peroxiredoxins and c-Myc

Graves, James; Metukuri, Mallikarjuna R.; Scott, Donald K.; Rothermund, Kristi; Prochownik, Edward V.

doi:10.1074/jbc.m807564200

Cited by 78 publications

(73 citation statements)

References 50 publications

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“…Upregulation of the GSH antioxidant metabolic pathway in p53-deficient MYCN-driven neuroblastoma suggested an increased requirement for detoxification of GST substrates, such as derivatives of ROS that are implicated in tumorigenesis, disease progression, and druginduced resistance (25). Furthermore, c-MYC overexpression and p53 loss of function have previously been shown to be associated with an alteration in ROS levels (2,(26)(27)(28). Consistent with these results, we found a significant increase in ROS-positive cells in Th-…”

Section: Mycn/trp53supporting

confidence: 79%

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

et al. 2016

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Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification of MYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare at diagnosis, but evidence suggests that p53 function is often impaired in relapsed, treatment-resistant disease. To address the role of p53 loss of function in the development and pathogenesis of high-risk neuroblastoma, we generated a MYCN-driven genetically engineered mouse model in which the tamoxifen-inducible p53ER TAM fusion protein was expressed from a knock-in allele (Th-MYCN/Trp53 KI ). We observed no significant differences in tumor-free survival between Th-MYCN mice heterozygous for Trp53 KI (n ¼ 188) and Th-MYCN mice with wild-type p53 (n ¼ 101). Conversely, the survival of Th-MYCN/Trp53 KI/KI mice lacking functional p53 (n ¼ 60) was greatly reduced. We found that Th-MYCN/Trp53 KI/KI tumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ER TAM reinstated sensitivity to IR in only 50% of Th-MYCN/ Trp53 KI/KI tumors, indicating the acquisition of additional resistance mechanisms. Gene expression and metabolic analyses indicated that the principal acquired mechanism of resistance to IR in the absence of functional p53 was metabolic adaptation in response to chronic oxidative stress. Tumors exhibited increased antioxidant metabolites and upregulation of glutathione S-transferase pathway genes, including Gstp1 and Gstz1, which are associated with poor outcome in human neuroblastoma. Accordingly, glutathione depletion by buthionine sulfoximine together with restoration of p53 activity resensitized tumors to IR. Our findings highlight the complex pathways operating in relapsed neuroblastomas and the need for combination therapies that target the diverse resistance mechanisms at play. Cancer Res; 76(10); 3025-35. Ó2016 AACR.

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Section: Mycn/trp53supporting

confidence: 79%

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

et al. 2016

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“…Indeed, there are several reports indicating that PRX-I inactivation results in the elevation of ROS levels and oxidative DNA damage (Neumann et al, 2003;Egler et al, 2005;Rhee et al, 2005;Graves et al, 2009). However, we showed here a quite unexpected PRX-I function, linking ROS to cell death.…”

Section: Discussionsupporting

confidence: 44%

“…The Hippo pathway appears to be conserved in mammals, and the human genes for several pathway components have been found to be mutated in cancers (O'Neill et al, 2005;Harvey and Tapon, 2007;Zeng and Hong, 2008). PRX-I is also suggested to suppress cancer development because mice lacking the PRX-I gene have a short life span owing to frequent development of several cancers (Neumann et al, 2003;Egler et al, 2005;Graves et al, 2009). In these reports, oncogenesis has been attributed to loss of PRX-I peroxidase activity.…”

Section: Discussionmentioning

confidence: 99%

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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Mammalian Ste20-like kinase-1 (MST1) kinase mediates H 2 O 2 -induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H 2 O 2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H 2 O 2 -induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H 2 O 2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H 2 O 2 -induced MST1 activation. Live-cell imaging showed H 2 O 2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H 2 O 2 -induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.

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“…Raji and HL-60 cells both have amplification of the c-Myc protooncogene (30 -32), which has been associated with increased intracellular levels of ROS (19,(32)(33)(34). We therefore analyzed the levels of intracellular hydrogen peroxide in both cell lines using the H2-DCFDA assay (27).…”

Section: Ros-dependent Oligomerization Of Ns-mentioning

confidence: 99%

Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

Huang¹,

Whang²,

Chodaparambil

et al. 2011

Journal of Biological Chemistry

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Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H 2 O 2 ) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H 2 O 2 impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation of NS by ROS was validated in a murine lymphoma tumor model in which c-Myc is overexpressed and in CD34؉ cells from patients with chronic myelogenous leukemia in blast crisis. In both instances, increased ROS levels were associated with markedly increased expression of NS protein and thiol-reversible oligomerization. Site-directed mutagenesis of critical cysteinecontaining regions of nucleostemin altered both its intracellular localization and its stability. MG132, a potent proteasome inhibitor and activator of ROS, markedly decreased degradation and increased nucleolar retention of NS mutants, whereas N-acetyl-L-cysteine largely prevented the effects of MG132. These results indicate that NS is a highly redox-sensitive protein. Increased intracellular ROS levels, such as those that result from oncogenic transformation in hematopoietic malignancies, regulate the ability of NS to oligomerize, prevent its degradation, and may alter its ability to regulate cell proliferation.Nucleostemin (NS) is a GTP-binding nucleolar protein that has been implicated in a variety of cellular processes, including cell cycle progression involving the G 1 -S (1, 2) and G 2 -M transitions (3), pre-rRNA processing (4), stress responses involving nucleoplasmic translocation (5, 6), cellular senescence (7), and inhibition of cell proliferation (8). NS shuttles from the nucleolus to the nucleoplasm in response to a variety of cellular stressors, including inhibition of RNA synthesis (5). We have recently demonstrated that reduction of intracellular GTP levels results not only in the nuclear translocation of NS, as had been observed previously (6), but also its rapid proteasomal degradation in an apparent Mdm2-dependent manner (9). A number of nuclear proteins interact with nucleostemin (10), including p53 (1, 8), Mdm2 (2, 3), ribosomal L1 domain-containing 1 (RSL1D1) (11), and telomeric repeat binding factor 1 (TRF-1) (7, 12). The regulation of these diverse proteins through their interactions with NS results in functional alterations in cell cycle control and telomere maintenance (10), although the precise mechanisms of regulation remain to be elucidated. Complete loss of NS, either through siRNA knockdown experiments (1, 2, 13, 14) or through it...

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Regulation of Reactive Oxygen Species Homeostasis by Peroxiredoxins and c-Myc

Cited by 78 publications

References 50 publications

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

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