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.
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Seetharaman
S
Balasenthil
Anupama E
AE
Gururaj
Amjad H
AH
Talukder
Rozita
R
Bagheri-Yarmand
Ty
T
Arrington
Brian J
BJ
Haas
John C
JC
Braisted
Insun
I
Kim
Norman H
NH
Lee
Rakesh
R
Kumar
D000818:Animals; D015152:Blotting, Northern; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D051757:PAX5 Transcription Factor / Q000235:genetics*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C503336:Mta1 protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases