Lutterbach B, Westendorf J J, Linggi B, Patten A, Moniwa M, Davie J R, Huynh K D, Bardwell V J, Lavinsky R M, Rosenfeld M G, Glass C, Seto E, Hiebert S W
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Mol Cell Biol. 1998 Dec;18(12):7176-84. doi: 10.1128/MCB.18.12.7176.
t(8;21) is one of the most frequent translocations associated with acute myeloid leukemia. It produces a chimeric protein, acute myeloid leukemia-1 (AML-1)-eight-twenty-one (ETO), that contains the amino-terminal DNA binding domain of the AML-1 transcriptional regulator fused to nearly all of ETO. Here we demonstrate that ETO interacts with the nuclear receptor corepressor N-CoR, the mSin3 corepressors, and histone deacetylases. Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes. Deletion mutagenesis indicates that ETO interacts with mSin3A independently of its association with N-CoR. Single amino acid mutations that impair the ability of ETO to interact with the central portion of N-CoR affect the ability of the t(8;21) fusion protein to repress transcription. Finally, AML-1/ETO associates with histone deacetylase activity and a histone deacetylase inhibitor impairs the ability of the fusion protein to repress transcription. Thus, t(8;21) fuses a component of a corepressor complex to AML-1 to repress transcription.
t(8;21)是与急性髓系白血病相关的最常见易位之一。它产生一种嵌合蛋白，即急性髓系白血病-1（AML-1）-八二十一（ETO），该蛋白包含与几乎所有ETO融合的AML-1转录调节因子的氨基末端DNA结合结构域。在这里，我们证明ETO与核受体共抑制因子N-CoR、mSin3共抑制因子和组蛋白脱乙酰酶相互作用。内源性ETO在蔗糖梯度上也与mSin3A、N-CoR和组蛋白脱乙酰酶共沉降，表明它是一种或多种共抑制复合物的组成部分。缺失诱变表明ETO与mSin3A相互作用，而不依赖于其与N-CoR的结合。损害ETO与N-CoR中央部分相互作用能力的单氨基酸突变会影响t(8;21)融合蛋白抑制转录的能力。最后，AML-1/ETO与组蛋白脱乙酰酶活性相关，组蛋白脱乙酰酶抑制剂会损害融合蛋白抑制转录的能力。因此，t(8;21)将一种共抑制复合物的成分与AML-1融合以抑制转录。
