E protein silencing by the leukemogenic AML1-ETO fusion protein
E protein silencing by the leukemogenic AML1-ETO fusion protein
复制标题
DOI：
10.1126/science.1097937
复制
发表时间：
2004-08-27
期刊：
影响因子：
56.9
通讯作者：
Roeder, RG
中科院分区：
文献类型：
--
作者：
Zhang, JS;Kalkum, M;Roeder, RG
由t（8;21）染色体易位产生的AML1-ETO融合蛋白与近15%的急性髓性白血病（AML）病例有因果关系。这项研究表明，AML1-ETO以及ETO通过稳定的相互作用抑制E蛋白的转录激活，这种相互作用阻止了p300/ creb结合蛋白（CBP）共激活因子的募集。这些相互作用是由一个保守的ETO TAF4同源结构域和一个17个氨基酸的p300/CBP和ETO靶基序在E蛋白的AD1激活域中介导的。在t（8;21）白血病细胞中，AML1-ETO和E蛋白之间非常稳定的相互作用是t（8;21）易位特异性沉默E蛋白功能的基础，通过异常的辅因子交换机制。这些研究确定了E蛋白作为AML1-ETO靶点，其失调可能对t（8;21）白血病发生很重要，以及不同于与分化抑制蛋白相关的E蛋白沉默机制。
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 15% of acute myeloid leukemia (AML) cases. This study shows that AML1-ETO, as well as ETO, inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of p300/CREB-binding protein (CBP) coactivators. These interactions are mediated by a conserved ETO TAF4 homology domain and a 17-amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In t(8;21) leukemic cells, very stable interactions between AML1-ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from that associated with differentiation-inhibitory proteins.