Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signaling

• Published in: Blood Vol. 102; no. 13; pp. 4555 - 4562
• Main Authors: Lebigot, Ingrid, Gardellin, Paola, Lefebvre, Laurent, Beug, Hartmut, Ghysdael, Jacques, Quang, Christine Tran
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.12.2003; The Americain Society of Hematology
• Subjects: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; bcl-X Protein; Biological and medical sciences; Cell Differentiation; Cell Transformation, Viral; Cells, Cultured; Chickens; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - physiology; Hematologic and hematopoietic diseases; Humans; Kidney; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Macromolecular Substances; Medical sciences; Milk Proteins; Molecular Sequence Data; Proto-Oncogene Protein c-fli-1; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins pp60(c-src) - biosynthesis; Proto-Oncogene Proteins pp60(c-src) - genetics; Proto-Oncogene Proteins pp60(c-src) - physiology; Receptors, Erythropoietin - antagonists & inhibitors; Receptors, Erythropoietin - physiology; Recombinant Fusion Proteins - physiology; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; STAT5 Transcription Factor; Trans-Activators - metabolism; Trans-Activators - physiology; Transfection; Erythropoiesis; Erythropoietin; Glycoprotein hormone; Erythroblast; Signal transduction; Vertebrata; Regulation(control); Transcription factor FLI-1; Animal; Malignant transformation; Chicken; Src like adaptor protein; Aves; Transcription factor; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-06-2077

Rearrangement of theFLI-1locus 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 thatSLAP, 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 antiapoptoticBCL-Xgene. 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. (Blood. 2003; 102:4555-4562)