Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway

Naughton, Ruth; Quiney, Claire; Turner, Suzanne D.; Cotter, Thomas G.

doi:10.1038/leu.2009.49

Cited by 138 publications

(138 citation statements)

References 37 publications

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“…In this regard, it has recently been shown that the inhibition of PP1a by ROS leads to the constitutive activation of the PI3K/ AKT pathway in leukaemic cells. 33 In addition, it has been shown that ROS are also important for platelet release, 34 this points to the importance of ROS not only in triggering differentiation programmes but also in terminal platelet release from mature megakaryocytes.…”

Section: Discussionmentioning

confidence: 99%

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34 þ cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22 phoxdependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.

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Section: Discussionmentioning

confidence: 99%

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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“…NOX-originated ROS have been documented to have multiple effects on leukemia cell proliferation and survival (13,19,27). Leukemic oncogenes have been shown to regulate either the expression of NOX components or the availability of their substrate.…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase-generated Hydrogen Peroxide Induces DNA Damage in Mutant FLT3-expressing Leukemia Cells

Stanicka

Russell

Woolley

et al. 2015

Journal of Biological Chemistry

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Background: NADPH oxidase is a hydrogen peroxide-generating enzyme, involved in redox signaling in cancer. Results: NADPH oxidase-generated hydrogen peroxide increases DNA damage and genomic instability. Conclusion: NADPH oxidase-derived hydrogen peroxide mediates DNA damage in acute myeloid leukemia (AML). Significance: The mechanism of DNA damage generation is important for studying aggressive AML phenotypes.

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“…Increased levels of ROS also result from the expression of oncogenes (19,20). The BCR-ABL translocation that results in chronic myelogenous leukemia (CML) has been shown to increase ROS levels in both BCR-ABL-transformed hematopoietic cell lines and primary CML cells (21)(22)(23). Mutations within the BCR-ABL tyrosine kinase domain that lead to resistance to imatinib as well as to other manifestations of DNA damage are accelerated by ROS generation and reduced by the concomitant administration of antioxidants (23).…”

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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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Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway

Cited by 138 publications

References 37 publications

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

NADPH Oxidase-generated Hydrogen Peroxide Induces DNA Damage in Mutant FLT3-expressing Leukemia Cells

Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

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