AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues
AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues
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DOI：
10.1074/jbc.m400355200
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发表时间：
2004-04-09
影响因子：
4.8
通讯作者：
Hirai, H
中科院分区：
文献类型：
--
作者：
Yamaguchi, Y;Kurokawa, M;Hirai, H
AML 1（RUNX 1）是人类白血病中最常被破坏的基因之一。AML 1编码的转录因子在造血分化中起关键作用，其不适当表达与造血细胞的白血病转化有关。先前的研究表明，转录辅因子p300结合到AML 1的C-末端区域，并在髓样细胞分化过程中刺激AML 1依赖性转录。在这里，我们报告，AML 1是特异性乙酰化的p300在体外。突变分析显示，p300在两个保守的赖氨酸残基（Lys-24和Lys-43）处乙酰化AML 1。AML 1在体内在相同位点发生乙酰化，并且p300介导的乙酰化显著增强AML 1的DNA结合活性。这两个赖氨酸的破坏严重损害了AML 1的DNA结合，并降低了AML 1的转录活性和转化潜力。综上所述，这些数据表明，通过p300的AML 1的乙酰化是一个关键的翻译后修饰的方式，并确定了一个新的机制，调节AML 1的功能。
AML1 (RUNX1) is one of the most frequently disrupted genes in human leukemias. AML1 encodes transcription factors, which play a pivotal role in hematopoietic differentiation, and their inappropriate expression is associated with leukemic transformation of hematopoietic cells. Previous studies demonstrated that the transcription cofactor p300 binds to the C-terminal region of AML1 and stimulates AML1-dependent transcription during myeloid cell differentiation. Here, we report that AML1 is specifically acetylated by p300 in vitro. Mutagenesis analyses reveal that p300 acetylates AML1 at the two conserved lysine residues (Lys-24 and Lys-43). AML1 is subject to acetylation at the same sites in vivo, and p300-mediated acetylation significantly augments the DNA binding activity of AML1. Disruption of these two lysines severely impairs DNA binding of AML1 and reduced the transcriptional activity and the transforming potential of AML1. Taken together, these data indicate that acetylation of AML1 through p300 is a critical manner of posttranslational modification and identify a novel mechanism for regulating the function of AML1.