Enhanced TNF-α-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1

Khadijeh Bijangi-Vishehsaraei, M. Reza Saadatzadeh, Adam Werne, Kristina A Wilson McKenzie, Reuben Kapur, Hidenori Ichijo, Laura Haneline

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Fanconi anemia (FA) is a chromosomal instability disorder characterized by progressive bone marrow failure. Experimental evidence suggests that enhanced oxidant and myelosuppressive cytokinemediated apoptosis of hematopoietic stem and progenitor cells contributes to the pathogenesis of marrow failure in FA. However, the molecular mechanisms responsible for the apoptotic phenotype in hematopoietic cells are incompletely understood. Recent data in Fancc -/- murine embryonic fibroblasts (MEFs) implicate increased oxidant-induced apoptotic signaling through the redox-dependent protein, apoptosis signal-regulating kinase 1 (Ask1). Here, we examined whether altered Ask1 signaling participated in the proapoptotic phenotype of primary Fancc -/- MEFs and hematopoietic progenitors treated with the myelosuppressive cytokine tumor necrosis factor-α (TNF-α). Our data indicate that TNF-α induces hyperactivation of Ask1 and the downstream effector p38 in Fancc-/- MEFs. In addition, Ask1 inactivation in Fancc-/- MEFs and hematopoietic progenitors restored survival to wild-type (WT) levels in the presence of TNF-α. Furthermore, targeting the Ask1 pathway by using either antioxidants or a p38 inhibitor protected Fancc-/- MEFs and c-kit+ cells from TNF-α-induced apoptosis. Collectively, these data argue that the predisposition of Fancc -/- hematopoietic progenitors to apoptosis is mediated in part through altered redox regulation and Ask1 hyperactivation.

Original languageEnglish
Pages (from-to)4124-4130
Number of pages7
JournalBlood
Volume106
Issue number13
DOIs
StatePublished - Dec 15 2005

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MAP Kinase Kinase Kinase 5
Fanconi Anemia
Fibroblasts
Tumor Necrosis Factor-alpha
Apoptosis
Hematopoietic Stem Cells
Oxidants
Oxidation-Reduction
Bone Marrow
Chromosome Disorders
Phenotype
Chromosomal Instability
Bone
Antioxidants
Cytokines

ASJC Scopus subject areas

  • Hematology

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Enhanced TNF-α-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1. / Bijangi-Vishehsaraei, Khadijeh; Saadatzadeh, M. Reza; Werne, Adam; McKenzie, Kristina A Wilson; Kapur, Reuben; Ichijo, Hidenori; Haneline, Laura.

In: Blood, Vol. 106, No. 13, 15.12.2005, p. 4124-4130.

Research output: Contribution to journalArticle

Bijangi-Vishehsaraei, Khadijeh ; Saadatzadeh, M. Reza ; Werne, Adam ; McKenzie, Kristina A Wilson ; Kapur, Reuben ; Ichijo, Hidenori ; Haneline, Laura. / Enhanced TNF-α-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1. In: Blood. 2005 ; Vol. 106, No. 13. pp. 4124-4130.
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