Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signaling.
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.
Lebigot
Ingrid
I
Institut Curie, Bat 110, Centre Universitaire, 91405 Orsay, France.
Gardellin
Paola
P
Lefebvre
Laurent
L
Beug
Hartmut
H
Ghysdael
Jacques
J
Quang
Christine Tran
CT
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007668:Kidney; D046911:Macromolecular Substances; D008894:Milk Proteins; D008969:Molecular Sequence Data; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050799:STAT5 Transcription Factor; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D051020:bcl-X Protein
D048868:Adaptor Proteins, Signal Transducing; C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D008894:Milk Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; C490635:SLA protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051020:bcl-X Protein; D016392:Proto-Oncogene Proteins pp60(c-src)