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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4124-4130.
Prepublished online as a Blood First Edition Paper on August 18, 2005; DOI 10.1182/blood-2005-05-2096.
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Submitted May 24, 2005
Accepted August 10, 2005
Enhanced TNF- induced apoptosis in Fanconi anemia type C deficient cells is dependent on apoptosis signal-regulating kinase 1
Khadijeh Bijangi-Vishehsaraei, M R Saadatzadeh, Adam Werne, Kristina A Wilson McKenzie, Reuben Kapur, Hidenori Ichijo, and Laura S Haneline*
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
University of Tokyo and CREST, Tokyo, Japan
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
* Corresponding author; email: lhanelin{at}iupui.edu.
Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow failure. Experimental evidence suggest that enhanced oxidant and myelosuppressive cytokine mediated apoptosis of hematopoietic stem and progenitor cells contribute to the pathogenesis of marrow failure in FA. However, the molecular mechanism(s) 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 pro-apoptotic phenotype of primary Fancc -/- MEFs and hematopoietic progenitors treated with the myelosuppressive cytokine, TNF- . Our data indicate that TNF- 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 WT levels in the presence of TNF-. Furthermore, targeting the ASK1 pathway by using either antioxidants or a p38 inhibitor protected Fancc -/- MEFs and ckit+ cells from TNF- 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.
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