title: Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent terminal differentiation.
abstract: The non-receptor protein tyrosine kinase Syk (spleen tyrosine kinase) is an important mediator of signal transduction in B cells. By acting downstream of the B-cell antigen receptor, Syk promotes signaling pathways involved in proliferation, differentiation and survival of B cells. To study the oncogenic potential of Syk, we generated a mouse model for the inducible expression of the leukemia-derived TEL-Syk fusion protein exhibiting constitutive kinase activity. To achieve B-cell-specific expression of TEL-Syk in adult mice, we used a tamoxifen-inducible Cre mouse line. This study shows that inducible expression of TEL-Syk in B cells leads to transient proliferation and subsequent plasma cell differentiation. However, it does not lead to B-cell transformation. Instead, Syk activation induces the tumor suppressor B-lymphocyte-induced maturation protein-1 (Blimp-1), which interferes with the expression of the antiapoptotic protein Bcl-2. Combined induction of TEL-Syk with transgenic expression of Bcl-2 results in a severe phenotype and plasma cell expansion. Our results suggest that deregulated Syk activity by itself is not sufficient for the transformation of B cells, as downstream effectors, such as Blimp-1, limit the survival and expansion of the activated B cell.
authors: 1] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität, Freiburg, Germany [2] Department of Molecular Immunology, Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany [3] Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors: E
authors: E
authors: Hug
authors: 1] Department of Molecular Immunology, Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany [2] Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors: E
authors: E
authors: Hobeika
authors: 1] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität, Freiburg, Germany [2] Department of Molecular Immunology, Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany [3] Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors: M
authors: M
authors: Reth
authors: 1] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität, Freiburg, Germany [2] Department of Molecular Immunology, Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany [3] Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors: H
authors: H
authors: Jumaa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D015870:Gene Expression / Q000187:drug effects; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010950:Plasma Cells / Q000166:cytology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D000072377:Syk Kinase; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; C513258:Prdm1 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D013629:Tamoxifen; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C045073:Cre recombinase; D019426:Integrases