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Type of publication: Journal Article
Type of document: Full Paper

Year: 2008

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

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

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

Authors Vetmeduni Vienna:

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

Vetmed Research Units
Institute of Animal Breeding and Genetics

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
Janus Kinase 2*
Mice, Knockout
Proto-Oncogene Proteins c-kit/metabolism
Receptors, Erythropoietin*
STAT5 Transcription Factor/metabolism*

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