Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains
Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains
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DOI：
10.1093/emboj/18.6.1609
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发表时间：
1999-03-15
期刊：
影响因子：
11.4
通讯作者：
Ito, Y
中科院分区：
文献类型：
--
作者：
Kim, WY;Sieweke, M;Ito, Y
转录因子Ets-1和AML 1（PEBP 2/CBF的α B1亚基）在造血和白血病发生中起关键作用，并在T细胞受体（TCR）β链增强子的反式激活中协同作用。这两种因子的DNA结合能力在分子内被阻断，但可以通过去除负调控结构域来激活。这些包括Ets-1的外显子VII结构域和α B1的DNA结合负调控结构域（NRDB）。在这里，我们报告，这两个因素之间的直接相互作用，导致其DNA结合活性和激活其反式激活功能的相互刺激，详细的映射揭示了两个独立的接触点，涉及外显子VII和NRDB区域以及两个DNA结合结构域。使用缺失变体和显性干扰突变体，我们证明了外显子VII和NRDB之间的相互作用是必要的和足够的合作DNA结合。外显子VH和NRDB基序在进化中高度保守，但在天然变体中缺失，这表明所描述的机制具有生物学相关性。Ets和AML 1通过自身抑制结构域的分子间相互作用相互激活DNA结合，这可能代表了转录因子功能调节的新原理。
The transcription factors Ets-1 and AML1 (the alpha B1 subunit of PEBP2/CBF) play critical roles in hematopoiesis and leukemogenesis, and cooperate in the transactivation of the T cell receptor (TCR) beta chain enhancer. The DNA binding capacity of both factors is blocked intramolecularly but can be activated by the removal of negative regulatory domains. These include the exon VII domain for Ets-l and the negative regulatory domain for DNA binding (NRDB) for alpha B1. Here we report that the direct interaction between the two factors leads to a reciprocal stimulation of their DNA binding activity and activation of their transactivation function, Detailed mapping revealed two independent contact points involving the exon VII and NRDB regions as well as the two DNA binding domains. Using deletion variants and dominant interfering mutants, we demonstrate that the interaction between exon VII and NRDB is necessary and sufficient for cooperative DNA binding. The exon VH and NRDB motifs are highly conserved in evolution yet deleted in natural variants, suggesting that the mechanism described is of biological relevance. The mutual activation of DNA binding of Ets and AML1 through the intermolecular interaction of autoinhibitory domains may represent a novel principle for the regulation of transcription factor function.