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Blood, 19 March 2009, Vol. 113, No. 12, pp. 2655-2660. Prepublished online as a Blood First Edition Paper on January 23, 2009; DOI 10.1182/blood-2008-09-181420. This Article Full Text (PDF) All Versions of this Article: blood-2008-09-181420v1 113/12/2655    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Saadatzadeh, M. R. Articles by Haneline, L. S. Search for Related Content PubMed PubMed Citation Articles by Saadatzadeh, M. R. Articles by Haneline, L. S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 26, 2008 Accepted January 15, 2009 Distinct roles of stress-activated protein kinases in Fanconi anemia type C deficient hematopoiesis M. Reza Saadatzadeh, Khadijeh Bijangi-Vishehsaraei, Reuben Kapur, and Laura S. Haneline* Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, IN, United States * Corresponding author; email: lhanelin{at}iupui.edu. The underlying molecular mechanisms that promote bone marrow (BM) failure in Fanconi anemia (FA) are incompletely understood. Evidence suggest that enhanced apoptosis of hematopoietic precursors is a major contributing factor. Previously, enhanced apoptosis of FA 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 (MEFs), TNF- induced elevated JNK activity. Additionally, JNK inhibition protected Fancc -/- MEFs and ckit+ BM cells from TNF- induced apoptosis. Importantly, hematopoietic progenitor assays demonstrated that JNK inhibition enhanced Fancc -/- colony formation in the presence of TNF-. Competitive repopulation assays showed that Fancc -/- donor cells cultured with the JNK inhibitor had equivalent levels of donor chimerism compared to Fancc -/- donor cells cultured with the 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 -/- HSC 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. D. Milsom, B. Schiedlmeier, J. Bailey, M.-O. Kim, D. Li, M. Jansen, A. M. Ali, M. Kirby, C. Baum, L. J. Fairbairn, et al. Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells Blood, May 21, 2009; 113(21): 5111 - 5120. [Abstract] [Full Text] [PDF]

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