Abstract
The erythropoietin receptor (EpoR) is essential for production of red blood cells; a principal function of EpoR is to rescue committed erythroid progenitors from apoptosis. Stat5 is rapidly activated following EpoR stimulation, but its function in erythropoiesis has been unclear since adult Stat5a-/-5b-/- mice have normal steady-state hematocrit. Here we show that Stat5 is essential for the high erythropoietic rate during fetal development. Stat5a-/-5b-/- embryos are severely anemic; erythroid progenitors are present in low numbers, show higher levels of apoptosis, and are less responsive to Epo. These findings are explained by a crucial role for Stat5 in EpoR's antiapoptotic signaling: it mediates the immediate-early induction of Bcl-X(L) in erythroid cells through direct binding to the Bcl-X promoter.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anemia / genetics*
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Animals
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Apoptosis / genetics*
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Base Sequence
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Cell Line
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Consensus Sequence
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DNA-Binding Proteins / genetics*
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Enhancer Elements, Genetic / physiology
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Erythrocytes / cytology
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Erythrocytes / drug effects
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Erythropoietin / pharmacology
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Gene Expression Regulation, Developmental
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Genes, Immediate-Early / physiology
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Hematocrit
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Hematopoietic Stem Cells / cytology*
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Mice
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Mice, Knockout
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Milk Proteins*
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Promoter Regions, Genetic / physiology
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / metabolism
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STAT5 Transcription Factor
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Signal Transduction / genetics
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Trans-Activators / genetics*
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Transcription, Genetic / physiology
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bcl-X Protein
Substances
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Bcl2l1 protein, mouse
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DNA-Binding Proteins
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Milk Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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STAT5 Transcription Factor
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Stat5a protein, mouse
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Trans-Activators
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bcl-X Protein
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Erythropoietin