A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution

被引:58
作者
Halupa, A
Bailey, ML
Huang, K
Iscove, NN
Levy, DE
Barber, DL
机构
[1] Univ Hlth Network, Div Cellular & Mol Biol, Ontario Canc Inst, Dept Lab Med & Pathobiol, Toronto, ON M5G 2M9, Canada
[2] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
[4] NYU, Dept Pathol, New York, NY 10016 USA
关键词
D O I
10.1182/blood-2003-09-3237
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Erythropoietin (EPO) activates many distinct signal transduction cascades on engagement of its receptor. Deletion of the EPO, EPO receptor (EPO-R), or JAK2 genes in mice results in embryonic lethality due to a fatal anemia. EPO activates signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a/b transcription factors in erythroid cell lines. Studies have focused on STAT5 as the primary target of EPO-dependent JAK2 activation. However, STAT5a/b(-/-) mice are viable, displaying a nonfatal anemia during embryogenesis, and delayed differentiation in adult erythropoiesis. Importantly, EPO-R cytoplasmic tyrosines are dispensable for viability in vivo. Interestingly, no cytoplasmic tyrosines are required for phosphorylation of STAT1. This led us to examine whether STAT1-deficient mice have altered erythropoiesis. A shift in erythropoiesis was observed in STAT1(-/-) mice, with reduced bone marrow-derived erythroid colony-forming units (CFU-Es) and a compensatory increase in splenic burst-forming units (BFU-Es) and CFU-Es. Both types of splenic-derived cells displayed EPO hyperresponsiveness. A 1.6-fold reduction in total CFU-Es was observed in STAT1-deficient mice, whereas total BFU-Es were comparable. Flow cytometry of STAT1-deficient erythroid cells revealed a less differentiated phenotype, associated with increased apoptosis of early erythroblasts. STAT1-deficient erythroblasts from phenylhydrazine-primed mice displayed enhanced phosphorylation of STAT5a/b, Erk1/2, and protein kinase B (PKB)/Akt. These results illustrate that STAT1 plays an important role in the regulation of erythropoiesis. (C) 2005 by The American Society of Hematology.
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收藏
页码:552 / 561
页数:10
相关论文
共 45 条
[1]   ERYTHROPOIETIN AND INTERLEUKIN-2 ACTIVATE DISTINCT JAK KINASE FAMILY MEMBERS [J].
BARBER, DL ;
DANDREA, AD .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (10) :6506-6514
[2]   A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation [J].
Barber, DL ;
Beattie, BK ;
Mason, JM ;
Nguyen, MHH ;
Yoakim, M ;
Neel, BG ;
D'Andrea, AD ;
Frank, DA .
BLOOD, 2001, 97 (08) :2230-2237
[3]  
BROXMEYER HE, 1985, J IMMUNOL, V135, P2502
[4]   TYROSINE-343 IN THE ERYTHROPOIETIN RECEPTOR POSITIVELY REGULATES ERYTHROPOIETIN-INDUCED CELL-PROLIFERATION AND STAT5 ACTIVATION [J].
DAMEN, JE ;
WAKAO, H ;
MIYAJIMA, A ;
KROSL, J ;
HUMPHRIES, RK ;
CUTLER, RL ;
KRYSTAL, G .
EMBO JOURNAL, 1995, 14 (22) :5557-5568
[5]   EXPRESSION CLONING OF THE MURINE ERYTHROPOIETIN RECEPTOR [J].
DANDREA, AD ;
LODISH, HF ;
WONG, GG .
CELL, 1989, 57 (02) :277-285
[6]   Targeted disruption of the mouse STAT1 results in compromised innate immunity to viral disease [J].
Durbin, JE ;
Hackenmiller, R ;
Simon, MC ;
Levy, DE .
CELL, 1996, 84 (03) :443-450
[7]   Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation [J].
Gobert, S ;
Chretien, S ;
Gouilleux, F ;
Muller, O ;
Pallard, C ;
DusanterFourt, I ;
Groner, B ;
Lacombe, C ;
Gisselbrecht, S ;
Mayeux, P .
EMBO JOURNAL, 1996, 15 (10) :2434-2441
[9]   PROLACTIN, GROWTH-HORMONE, ERYTHROPOIETIN AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR INDUCE MGF-STAT5 DNA-BINDING ACTIVITY [J].
GOUILLEUX, F ;
PALLARD, C ;
DUSANTERFOURT, I ;
WAKAO, H ;
HALDOSEN, LA ;
NORSTEDT, G ;
LEVY, D ;
GRONER, B .
EMBO JOURNAL, 1995, 14 (09) :2005-2013
[10]   Regulation of erythropoietin-induced STAT serine phosphorylation by distinct mitogen-activated protein kinases [J].
Haq, R ;
Halupa, A ;
Beattie, BK ;
Mason, JM ;
Zanke, BW ;
Barber, DL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (19) :17359-17366