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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4511-4522. Prepublished online as a Blood First Edition Paper on January 31, 2008; DOI 10.1182/blood-2007-07-102848. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2007-07-102848v1 111/9/4511    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Grebien, F. Articles by Moriggl, R. PubMed PubMed Citation Articles by Grebien, F. Articles by Moriggl, R. Related Collections Hematopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2 Florian Grebien1, Marc A. Kerenyi1, Boris Kovacic2, Thomas Kolbe3,4, Verena Becker5, Helmut Dolznig6, Klaus Pfeffer7, Ursula Klingmüller5, Mathias Müller3,8, Hartmut Beug2, Ernst W. Müllner1,*, and Richard Moriggl9,* 1 Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria; 2 Research Institute of Molecular Pathology, Vienna, Austria; 3 Biomodels Austria, Veterinary University Vienna, Vienna, Austria; 4 Department of Agrobiotechnology, IFA (Interuniversitären Forschungsinstitutes für Agrarbiotechnologie)–Tulln, Biotechnology in Animal Production, University of Natural Resources and Applied Life Sciences, Vienna, Austria; 5 German Cancer Research Center, Heidelberg, Germany; 6 Institute of Pathology, Medical University of Vienna, Vienna, Austria; 7 Institute of Medical Microbiology, Heinrich-Heine University, Duesseldorf, Germany; 8 Institute of Animal Breeding and Genetics, Veterinary University Vienna, Vienna, Austria; and 9 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2–/– and EpoR–/– cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a–estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2–/– fetal livers, transplantation of Jak2–/–-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine- and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropoiesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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