Identification of Pax5 as a target of MTA1 in B-cell lymphomas.
Previously, we have shown that metastasis-associated protein 1 (MTA1) overexpression in transgenic mice was accompanied by high incidence of spontaneous B-cell lymphomas including diffuse large B-cell lymphomas (DLBCL). To understand the molecular basis of lymphoma in MTA1-transgenic (MTA1-TG) mice, we wished to identify a putative MTA1 target with a causal ... role in B-cell lymphogenesis. Using chromatin immunoprecipitation assays, we identified paired box gene 5 (Pax5), a molecule previously implicated in B-cell lymphogenesis, as a potential downstream effector of MTA1. Lymphomas from MTA1-TG mice also showed up-regulation of Pax5. We also found that MTA1 acetylated on Lys(626) interacted with p300 histone acetyltransferase, and that acetylated MTA1 was recruited to the Pax5 promoter to stimulate Pax5 transcription. Global gene profiling identified down-regulation of a set of genes, including those downstream of Pax5 and directly implicated in the B-cell lymphogenesis. Significance of these murine studies was established by evidence showing a widespread up-regulation of both MTA1 and Pax5 in DLBCL from humans. These observations provide in vivo genetic evidence for a role of MTA1 in lymphomagenesis.
Mesh Terms:
Animals, B-Cell-Specific Activator Protein, Blotting, Northern, Chromatin Immunoprecipitation, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Histone Deacetylase 1, Histone Deacetylases, Humans, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, Transgenic, Mutagenesis, Site-Directed, Plasmids, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Transcriptional Activation, Transfection, Tumor Cells, Cultured
Animals, B-Cell-Specific Activator Protein, Blotting, Northern, Chromatin Immunoprecipitation, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Histone Deacetylase 1, Histone Deacetylases, Humans, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, Transgenic, Mutagenesis, Site-Directed, Plasmids, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Transcriptional Activation, Transfection, Tumor Cells, Cultured
Cancer Res.
Date: Aug. 01, 2007
PubMed ID: 17671180
View in: Pubmed Google Scholar
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