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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2008

AutorInnen: Grebien, F; Kerenyi, MA; Kovacic, B; Kolbe, T; Becker, V; Dolznig, H; Pfeffer, K; Klingmüller, U; Müller, M; Beug, H; Müllner, EW; Moriggl, R

Titel: Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2.

Quelle: Blood. 2008; 111(9):4511-4522



Autor/innen der Vetmeduni Vienna:

Beug Hartmut
Grebien Florian
Kolbe Thomas
Kovacic Boris
Moriggl Richard
Müller Mathias

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik


Abstract:
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.

Keywords Pubmed: Animals
Cells, Cultured
Cytokines/metabolism
Erythropoiesis*
Janus Kinase 2*
Mice
Mice, Knockout
Myelopoiesis
Proto-Oncogene Proteins c-kit/metabolism
Receptors, Erythropoietin*
STAT5 Transcription Factor/metabolism*


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