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

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

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Fanconi anemia is a genetic disorder characterized by bone marrow failure. Significant evidence supports enhanced apoptosis of hematopoietic stem/progenitor cells as a critical factor in the pathogenesis of bone marrow failure in Fanconi anemia. However, the molecular mechanism(s) responsible for the apoptotic phenotype are incompletely understood. Here, we tested whether alterations in the activation of a redox-dependent pathway may participate in the pro-apoptotic phenotype of primary Fancc -/- cells in response to oxidative stress. Our data indicate that Fancc -/- cells are highly sensitive to oxidant stimuli and undergo enhanced oxidant-mediated apoptosis compared with wild type controls. In addition, antioxidants preferentially enhanced the survival of Fancc -/- cells. Because oxidative stress activates the redox-dependent ASK1 pathway, we assessed whether Fancc -/- cells exhibited increased oxidant-induced ASK1 activation. Our results revealed ASK1 hyperactivation in H2O2-treated Fancc -/- cells. Furthermore, using small interfering RNAs to decrease ASK1 expression and a dominant negative ASK1 mutant to inhibit ASK1 kinase activity, we determined that H2O 2-induced apoptosis was ASK1-dependent. Collectively, these data argue that the predisposition of Fancc -/- hematopoietic stem/progenitor cells to apoptosis is mediated in part through altered redox regulation and ASK1 hyperactivation.

Original languageEnglish
Pages (from-to)16805-16812
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number16
DOIs
StatePublished - Apr 16 2004

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Fanconi Anemia
Hematopoietic Stem Cells
Oxidants
Oxidation-Reduction
Hypersensitivity
Apoptosis
Oxidative stress
Stem cells
Bone
Oxidative Stress
Bone Marrow
Chemical activation
Phenotype
Inborn Genetic Diseases
Small Interfering RNA
Cell Survival
Phosphotransferases
Antioxidants

ASJC Scopus subject areas

  • Biochemistry

Cite this

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.

In: Journal of Biological Chemistry, Vol. 279, No. 16, 16.04.2004, p. 16805-16812.

Research output: Contribution to journalArticle

Saadatzadeh, M. Reza ; Bijangi-Vishehsaraei, Khadijeh ; Hong, Ping ; Bergmann, Heidi ; Haneline, Laura. / Oxidant Hypersensitivity of Fanconi Anemia Type C-deficient Cells Is Dependent on a Redox-regulated Apoptotic Pathway. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 16. pp. 16805-16812.
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