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Blood, 1 July 2006, Vol. 108, No. 1, pp. 152-159. Prepublished online as a Blood First Edition Paper on March 9, 2006; DOI 10.1182/blood-2005-09-3866. This Article Full Text (PDF) All Versions of this Article: 2005-09-3866v1 108/1/152    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 Rubiolo, C. Articles by Baccarini, M. Search for Related Content PubMed PubMed Citation Articles by Rubiolo, C. Articles by Baccarini, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 27, 2005 Accepted February 23, 2006 A balance between Raf-1 And Fas expression sets the pace of erythroid differentiation Cristina Rubiolo, Daniela Piazzolla, Katrin Meissl, Hartmut Beug, Johannes C Huber, Andrea Kolbus, and Manuela Baccarini* Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine, Medical University of Vienna, Vienna, Austria Department of Microbiology & Immunobiology, Max F. Perutz Laboratories, University Departments of the Vienna Biocenter, Vienna, Austria Research Institute of Molecular Pathology, Vienna, Austria * Corresponding author; email: manuela.baccarini{at}univie.ac.at. Normal erythropoiesis critically depends on the balance between the renewal of precursor cells and their differentiation. If the renewal phase is shortened, the decrease in the precursor pool results in anemia; conversely, impaired differentiation increases the number of proliferating progenitors and the potential risk of leukemic transformation. Using gene ablation, we have discovered two self-sustaining signal transduction loops that antagonize each other and regulate erythroid progenitor proliferation and differentiation, respectively. We identify Raf-1 as the main activator of the MEK/ERK cascade and as the key molecule in maintaining progenitor proliferation. Differentiation, in contrast, is mediated by Fas via the activation of both the ASK1/JNK/p38 module and the caspase cascade. The point of convergence between the two cascades is activated ERK, which positively feeds back on the proliferation pathway by maintaining the expression of Raf-1, while inhibiting the expression of Fas and therefore differentiation. In turn Fas, once expressed, antagonizes proliferation by exerting a negative feedback on ERK activation and Raf-1 expression. Simultaneously, Fas-mediated caspase activation precipitates differentiation. These results identify Raf-1 and Fas as the key molecules whose expression finely tunes erythropoiesis, and the extent of ERK activation as the switch that tips the balance between them. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Bhatia, J. L. Hallock, A. Dutta, S. Karkashon, L. S. Sterner, T. Miyazaki, A. Dean, and J. A. Little Short-chain fatty acid-mediated effects on erythropoiesis in primary definitive erythroid cells Blood, June 18, 2009; 113(25): 6440 - 6448. [Abstract] [Full Text] [PDF] A. Elorza, B. Hyde, H. K. Mikkola, S. Collins, and O. S. Shirihai UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis J. Biol. Chem., November 7, 2008; 283(45): 30461 - 30470. [Abstract] [Full Text] [PDF] P. Rimmele, O. Kosmider, P. Mayeux, F. Moreau-Gachelin, and C. Guillouf Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation Blood, April 1, 2007; 109(7): 3007 - 3014. [Abstract] [Full Text] [PDF]

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