A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis
A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis
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DOI：
10.1038/nature01062
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发表时间：
2002-10-17
期刊：
影响因子：
64.8
通讯作者：
Brindle, PK
中科院分区：
文献类型：
--
作者：
Kasper, LH;Boussouar, F;Brindle, PK
共激活因子CBP（Cre-element binding protein（CREB）binding protein）及其辅助因子p300被认为为许多调节基因表达的转录因子提供衔接分子和蛋白乙酰转移酶功能（1）。正常发育需要CBP和p300，在造血和上皮肿瘤中发现了这些基因的突变（2-6）。然而，目前还不清楚CBP和p300的哪些功能在体内是必不可少的。在这里，我们表明CBP和p300的蛋白结合KIX结构域在小鼠中具有非冗余功能。在p300的KIX结构域中的点突变的纯合子小鼠中，该突变被设计为破坏转录因子c-Myb和CREB 7 -9的结合表面，在造血中发生多谱系缺陷，包括贫血、B细胞缺陷、胸腺发育不全、巨核细胞增多和血小板增多。相比之下，年龄匹配的CBP KIX结构域突变纯合子小鼠基本正常。c-Myb突变和p300 KIX结构域突变之间存在协同遗传相互作用，这表明c-Myb与p300该结构域的结合对巨核细胞的发育和功能至关重要。因此，在两个高度相关的辅激活因子的保守结构域在造血中具有相反的作用。
The coactivators CBP (Cre-element binding protein (CREB) binding protein) and its paralogue p300 are thought to supply adaptor molecule and protein acetyltransferase functions to many transcription factors that regulate gene expression(1). Normal development requires CBP and p300, and mutations in these genes are found in haematopoietic and epithelial tumours(2-6). It is unclear, however, which functions of CBP and p300 are essential in vivo. Here we show that the protein-binding KIX domains of CBP and p300 have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb and CREB7-9, multilineage defects occur in haematopoiesis, including anaemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-Myb and mutations in the KIX domain of p300, which suggests that the binding of c-Myb to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, conserved domains in two highly related coactivators have contrasting roles in haematopoiesis.