title: Distinct roles of stress-activated protein kinases in Fanconi anemia-type C-deficient hematopoiesis.
abstract: The underlying molecular mechanisms that promote bone marrow failure in Fanconi anemia are incompletely understood. Evidence suggests that enhanced apoptosis of hematopoietic precursors is a major contributing factor. Previously, enhanced apoptosis of Fanconi anemia type C-deficient (Fancc(-/-)) progenitors was shown to involve aberrant p38 MAPK activation. Given the importance of c-Jun N-terminal kinase (JNK) in the stress response, we tested whether enhanced apoptosis of Fancc(-/-) cells also involved altered JNK activation. In Fancc(-/-) murine embryonic fibroblasts, tumor necrosis factor alpha (TNF-alpha) induced elevated JNK activity. In addition, JNK inhibition protected Fancc(-/-) murine embryonic fibroblasts and c-kit(+) bone marrow cells from TNF-alpha-induced apoptosis. Importantly, hematopoietic progenitor assays demonstrated that JNK inhibition enhanced Fancc(-/-) colony formation in the presence of TNF-alpha. Competitive repopulation assays showed that Fancc(-/-) donor cells cultured with the JNK inhibitor had equivalent levels of donor chimerism compared with Fancc(-/-) donor cells cultured with vehicle control. In contrast, culturing Fancc(-/-) cells with a p38 MAPK inhibitor significantly increased repopulating ability, supporting an integral role of p38 MAPK in maintaining Fancc(-/-) hematopoietic stem cell function. Taken together, these data suggest that p38 MAPK, but not JNK, has a critical role in maintaining the engraftment of Fancc(-/-)-reconstituting cells under conditions of stress.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Saadatzadeh
authors.forename: Khadijeh
authors.initials: K
authors.lastname: Bijangi-Vishehsaraei
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Laura S
authors.initials: LS
authors.lastname: Haneline
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D005199:Fanconi Anemia / Q000201:enzymology* / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011828:Radiation Chimera; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580