Oxidant Hypersensitivity of Fanconi Anemia Type C-deficient Cells Is Dependent on a Redox-regulated Apoptotic Pathway

Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Hong, Ping; Bergmann, Heidi; Haneline, Laura S.

doi:10.1074/jbc.m313721200

Cited by 73 publications

(94 citation statements)

References 73 publications

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“…The FA proteins are thus believed to play important roles in the maintenance of hematopoiesis. Consistent with the observations that cells derived from FA patients are intolerant of oxidative stress, it has been reported that FA proteins, particularly the complementation group C (FANCC) protein, play a crucial role in oxidative-stress signaling in a variety of cell types including hematopoietic cells (Kruyt et al, 1998;Cumming et al, 2001;Hadjur et al, 2001;Futaki et al, 2002;Park et al, 2004;Saadatzadeh et al, 2004;Pagano et al, 2005). More recently, cytokine hypersensitivity of FA hematopoietic cells to apoptotic cues has also been proposed as a major factor in the pathogenesis of BM failure in three FA mouse models…”

Section: Introductionsupporting

confidence: 53%

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Sejas

Qiu

Williams

et al. 2007

Journal of Cell Science

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The proinflammatory cytokine tumor necrosis factor α (TNFα) inhibits hematopoietic stem cell (HSC) expansion, interferes with HSC self-renewal and compromises the ability of HSC to reconstitute hematopoiesis. We have investigated mechanisms by which TNFα suppresses hematopoiesis using the genomic instability syndrome Fanconi anemia mouse model deficient for the complementation-group-C gene (Fancc). Examination of senescence makers, such as senescence-associated β-galactosidase, HP1-γ, p53 and p16INK4A shows that TNFα induces premature senescence in bone marrow HSCs and progenitor cells as well as other tissues of Fancc–/– mice. TNFα-induced senescence correlates with the accumulation of reactive oxygen species (ROS) and oxidative DNA damage. Neutralization of TNFα or deletion of the TNF receptor in Fancc–/– mice (Fancc–/–;Tnfr1–/–) prevents excessive ROS production and hematopoietic senescence. Pretreatment of TNFα-injected Fancc–/– mice with a ROS scavenger significantly reduces oxidative base damage, DNA strand breaks and senescence. Furthermore, HSCs and progenitor cells from TNFα-treated Fancc–/– mice show increased chromosomal aberrations and have an impaired oxidative DNA-damage repair. These results indicate an intimate link between inflammatory reactive oxygen species and DNA-damage-induced premature senescence in HSCs and progenitor cells, which may play an important role in aging and anemia.

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Section: Introductionsupporting

confidence: 53%

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Sejas

Qiu

Williams

et al. 2007

Journal of Cell Science

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“…Ask1 plays an important role in the cell response to oxidative stress, being essential for the activation of the stressactivated protein kinase JNK (Gotoh and Cooper, 1998;Tobiume et al, 2001;Machino et al, 2003;Saadatzadeh et al, 2004;Kadowaki et al, 2005). As expected, exposure of HEK293 cells to H 2 O 2 induced the rapid phosphorylation of JNK ( Figure 1E), which was increased severalfold by pretransfecting the cells with a HA-tagged version of Ask1 (Ask1-HA) ( Figure 1A, lanes 3 and 4).…”

Section: In Vivo Oxidation Of Ask1 By H 2 Omentioning

confidence: 84%

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Nadeau

Charette

Toledano

et al. 2007

MBoC

171

137

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Apoptosis signal-regulated kinase-1 (Ask1) lies upstream of a major redox-sensitive pathway leading to the activation of Jun NH 2 -terminal kinase (JNK) and the induction of apoptosis. We found that cell exposure to H 2 O 2 caused the rapid oxidation of Ask1, leading to its multimerization through the formation of interchain disulfide bonds. Oxidized Ask1 was fully reduced within minutes after induction by H 2 O 2 . During this reduction, the thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) became covalently associated with Ask1. Overexpression of Trx1 accelerated the reduction of Ask1, and a redox-inactive mutant of Trx1 (C35S) remained trapped with Ask1, blocking its reduction. Preventing the oxidation of Ask1 by either overexpressing Trx1 or using an Ask1 mutant in which the sensitive cysteines were mutated (Ask1-⌬Cys) impaired the activation of JNK and the induction of apoptosis while having little effect on Ask1 activation. These results indicate that Ask1 oxidation is required at a step subsequent to activation for signaling downstream of Ask1 after H 2 O 2 treatment. INTRODUCTIONH 2 O 2 is emerging as an important intracellular signaling molecule affecting a variety of cellular responses. In mammals, H 2 O 2 concentration transiently increases in response to different membrane-receptor agonists such as peptide growth factors, hormones, cytokines, and neurotransmitters. This increase of H 2 O 2 concentration is important for downstream signaling from the corresponding membrane receptors (Deyulia et al., 2005;Rhee et al., 2005;Stone and Yang, 2006). Some of these H 2 O 2 regulatory effects are mediated by protein-thiol oxidation, as shown for the oxidative inhibition of protein tyrosine phosphatase upon receptor-tyrosine kinases engagement. H 2 O 2 can oxidize cysteine residues to the sulfenic (protein-SOH), sulfinic (protein-SO 2 H), and sulfonic acid (protein-SO 3 H) forms, also leading to intra-or intermolecular disulfide bonds (protein-SS-protein) and to protein glutathionylation (protein-SSG). Similarly to protein posttranslational modification by serine, threonine, and tyrosine phosphorylation, oxidation of cysteine residues can trigger changes in protein conformation and activity (Filomeni et al., 2005). In bacteria, OxyR is an archetypical H 2 O 2 sensor at the top of a redox-sensitive pathway, being activated by H 2 O 2 through formation of an intramolecular disulfide bond and controlling the transcription of antioxidant defense genes (Storz and Tartaglia, 1992;Zheng et al., 1998). In yeast, H 2 O 2 sensing involves the thiol-based peroxidase Orp1/Gpx3, which, upon oxidation by H 2 O 2 , mediates the formation of an intramolecular disulfide bond in the Yap1 transcription factor, causing its activation (Lee et al., 1999;Delaunay et al., 2002).The mitogen-activated protein kinase kinase kinase apoptosis signal-regulated kinase-1 (Ask1) and its downstream stress-activated kinases p38 and Jun NH 2 -terminal kinase (JNK) constitute an important mammalian signaling pathway that can promote cell surviv...

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“…Moreover, the role of inappropriate disulfide bond formation in the pathogenesis of human disease is relatively unknown. The physiological importance of maintaining key redox-sensitive proteins in a reduced state was recently demonstrated in studies showing that the Fanconi anemia group C protein increases the survival of hematopoietic progenitor cells by preventing disulfide bond formation and the concomitant inactivation of glutathione S-transferase P1 during apoptosis (30) in addition to preventing H 2 O 2 -induced activation of the redox-sensitive kinase ASK1 (57). The findings presented here highlight the pivotal role of cysteine oxidation and disulfide bond formation in many aspects of cell function during oxidative stress and should provide a basis for further exploration of the disulfide proteome.…”

Section: Discussionmentioning

confidence: 99%

Protein Disulfide Bond Formation in the Cytoplasm during Oxidative Stress

Cumming

Andon

Haynes

et al. 2004

Journal of Biological Chemistry

404

358

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The majority of disulfide-linked cytosolic proteins are thought to be enzymes that transiently form disulfide bonds while catalyzing oxidation-reduction (redox) processes. Recent evidence indicates that reactive oxygen species can act as signaling molecules by promoting the formation of disulfide bonds within or between select redox-sensitive proteins. However, few studies have attempted to examine global changes in disulfide bond formation following reactive oxygen species exposure. Here we isolate and identify disulfide-bonded proteins (DSBP) in a mammalian neuronal cell line (HT22) exposed to various oxidative insults by sequential nonreducing/reducing two-dimensional SDS-PAGE combined with mass spectrometry. By using this strategy, several known cytosolic DSBP, such as peroxiredoxins, thioredoxin reductase, nucleoside-diphosphate kinase, and ribonucleotide-diphosphate reductase, were identified. Unexpectedly, a large number of previously unknown DSBP were also found, including those involved in molecular chaperoning, translation, glycolysis, cytoskeletal structure, cell growth, and signal transduction. Treatment of cells with a wide range of hydrogen peroxide concentrations either promoted or inhibited disulfide bonding of select DSBP in a concentration-dependent manner. Decreasing the ratio of reduced to oxidized glutathione also promoted select disulfide bond formation within proteins from cytoplasmic extracts. In addition, an epitope-tagged version of the molecular chaperone HSP70 forms mixed disulfides with both ␤4-spectrin and adenomatous polyposis coli protein in the cytosol. Our findings indicate that disulfide bond formation within families of cytoplasmic proteins is dependent on the nature of the oxidative insult and may provide a common mechanism used to control multiple physiological processes.Oxidative stress occurs when the rate of reactive oxygen species (ROS) 1 generation exceeds the detoxification abilities of the cell, and it has been implicated in many degenerative diseases. It is frequently argued that ROS cause relatively nonspecific damage to vital cellular components such as lipids, DNA, and proteins. However, emerging evidence indicates that ROS can cause specific protein modifications that may lead to a change in the activity or function of the oxidized protein (1, 2). Several major forms of oxidative modifications can occur on amino acid residue side chains including carbonylation, nitrosylation, and oxidation of methionine to methionine sulfoxide (3). Protein sulfhydryls can be oxidized to protein disulfides and sulfenic acids as well as more highly oxidized states such as the sulfinic and sulfonic acid forms of protein cysteines (4). Under non-stressed conditions, disulfide bond formation occurs primarily in the oxidizing environment of the endoplasmic reticulum (ER) in eukaryotic cells (5). The sulfhydryl groups in the vast majority of protein cysteine residues (Cys-SH) have a pK a Ͼ8.0 and, in the reducing environment of the cytoplasm, remain protonated at physiological pH. Thus,...

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Oxidant Hypersensitivity of Fanconi Anemia Type C-deficient Cells Is Dependent on a Redox-regulated Apoptotic Pathway

Cited by 73 publications

References 73 publications

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis

Protein Disulfide Bond Formation in the Cytoplasm during Oxidative Stress

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Oxidant Hypersensitivity of Fanconi Anemia Type C-deficient Cells Is Dependent on a Redox-regulated Apoptotic Pathway

Cited by 73 publications

References 73 publications

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis

Protein Disulfide Bond Formation in the Cytoplasm during Oxidative Stress

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Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H₂O₂-induced c-Jun NH₂-terminal Kinase Activation and Apoptosis