Identification of Pax5 as a target of MTA1 in B-cell lymphomas
Identification of Pax5 as a target of MTA1 in B-cell lymphomas
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DOI：
10.1158/0008-5472.can-07-0750
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发表时间：
2007-08-01
期刊：
影响因子：
11.2
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Balasenthil, Seetharaman;Gururaj, Anupama E.;Kumar, Rakesh
此前，我们已经证明，在转基因小鼠中过度表达转移相关蛋白1(MTA1)会伴随着包括弥漫性大B细胞淋巴瘤(DLBCL)在内的自发性B细胞淋巴瘤的高发病率。为了了解MTA1转基因(MTA1-TG)小鼠淋巴瘤的分子基础，我们希望确定一个在B细胞淋巴发生中起因果作用的假定的MTA1靶点。利用染色质免疫沉淀分析，我们确定配对盒基因5(Pax5)是MTA1潜在的下游效应因子，Pax5是以前参与B细胞淋巴发生的分子。来自MTA1-TG小鼠的淋巴瘤也显示出Pax5的上调。我们还发现，在Lys(626)上乙酰化的MTA1与p300组蛋白乙酰转移酶相互作用，并且乙酰化的MTA1被招募到Pax5启动子以刺激Pax5转录。全球基因图谱发现了一系列基因的下调，包括Pax5下游的基因，并直接与B细胞的淋巴生成有关。这些小鼠研究的意义是通过证据表明人类在DLBCL中MTA1和Pax5的广泛上调而确立的。这些观察结果为MTA1在淋巴肿瘤发生中的作用提供了体内遗传学证据。
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.