Enhanced TNF-alpha-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1.
Fanconi anemia (FA) is a chromosomal instability disorder characterized by progressive bone marrow failure. Experimental evidence suggests that enhanced oxidant and myelosuppressive cytokine-mediated 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-alpha (TNF-alpha). Our data indicate that TNF-alpha 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-alpha. Furthermore, targeting the Ask1 pathway by using either antioxidants or a p38 inhibitor protected Fancc-/- MEFs and c-kit+ cells from TNF-alpha-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.
Bijangi-Vishehsaraei
Khadijeh
K
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, R4-476, 1044 W. Walnut St, Indianapolis, IN 46202, USA.
Saadatzadeh
M Reza
MR
Werne
Adam
A
McKenzie
Kristina A Wilson
KA
Kapur
Reuben
R
Ichijo
Hidenori
H
Haneline
Laura S
LS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D052218:Fanconi Anemia Complementation Group C Protein; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C093642:SB 203580