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 S. Haneline

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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