Abstract
Rearrangement of the FLI-1 locus and ensuing overexpression of FLI-1 protein is an early event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. When overexpressed in primary erythroblasts, FLI-1 converts erythropoietin (Epo)-induced terminal differentiation into a proliferative response. We found that SLAP, a gene encoding a recently described negative regulator of T-cell antigen receptor function during thymocyte development, is up-regulated both at the RNA and protein levels in FLI-1-transformed erythroblasts. Src-like adaptor protein (SLAP) was found in a specific complex with erythropoietin receptor (EpoR), a cytokine receptor essential to erythroid differentiation. Constitutive expression of SLAP severely impairs hemoglobinization and late survival during Epo-induced terminal differentiation of erythroblasts. This impairment is associated with the specific inhibition of several critical Epo-dependent signaling events, including signal transducer and activator of transcription 5 (STAT5) activation and up-regulation of the expression of the antiapoptotic BCL-X gene. Our data support a model by which FLI-1 inhibits normal erythroid differentiation through the deregulation of genes encoding adaptors/effectors that modify the signaling output of cytokine receptors normally required for terminal differentiation.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Animals
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Cell Differentiation
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Cell Transformation, Viral*
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Cells, Cultured
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Chickens
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Erythroid Precursor Cells / cytology
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Erythroid Precursor Cells / physiology*
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Humans
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Kidney
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Macromolecular Substances
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Milk Proteins*
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Molecular Sequence Data
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Proto-Oncogene Protein c-fli-1
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins pp60(c-src) / biosynthesis
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Proto-Oncogene Proteins pp60(c-src) / genetics
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Proto-Oncogene Proteins pp60(c-src) / physiology*
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Proto-Oncogene Proteins*
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Receptors, Erythropoietin / antagonists & inhibitors*
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Receptors, Erythropoietin / physiology
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Recombinant Fusion Proteins / physiology
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STAT5 Transcription Factor
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Sequence Alignment
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Sequence Homology, Amino Acid
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Signal Transduction
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transfection
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bcl-X Protein
Substances
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Adaptor Proteins, Signal Transducing
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BCL2L1 protein, human
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DNA-Binding Proteins
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Macromolecular Substances
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Milk Proteins
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Proto-Oncogene Protein c-fli-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Erythropoietin
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Recombinant Fusion Proteins
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SLA protein, human
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STAT5 Transcription Factor
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Trans-Activators
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bcl-X Protein
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Proto-Oncogene Proteins pp60(c-src)