The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain
The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain
复制标题
DOI：
10.1128/mcb.23.2.607-619.2003
复制
发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Hiebert, SW
中科院分区：
文献类型：
--
作者：
Durst, KL;Lutterbach, B;Hiebert, SW
倒位（16）是急性髓细胞白血病（AML）中最常见的染色体易位之一，发生在超过8%的AML病例中。这种易位导致蛋白产物将核心结合因子0的前165个氨基酸融合到平滑肌肌球蛋白重链的卷曲螺旋区（CBFbeta/SMMHC）。CBF β与AML 1相互作用形成异源二聚体，结合DNA;这种相互作用增加了AML 1对DNA的亲和力。CBF β/SMMHC融合蛋白与AML 1协同作用，抑制AML 1调节基因的转录。我们发现CBF β/SMMHC在SMMHC区域的C-末端163个氨基酸中含有抑制结构域，这是inv（16）介导的转录抑制所必需的。这种最小的阻遏结构域足以使CBF β/SMMHC与mSin 3A辅阻遏物结合。此外，inv（16）融合蛋白特异性地与组蛋白脱乙酰酶8（HDAC 8）结合。inv（16）介导的阻遏对HDAC抑制剂敏感。我们提出了一个模型，其中inv（16）融合蛋白与AML 1协会转化为一个组成型转录抑制AML 1。
Inversion(16) is one of the most frequent chromosomal translocations found in acute myeloid leukemia (AML), occurring in over 8% of AML cases. This translocation results in a protein product that fuses the first 165 amino acids of core binding factor 0 to the coiled-coil region of a smooth muscle myosin heavy chain (CBFbeta/SMMHC). CBFbeta interacts with AML1 to form a heterodimer that binds DNA; this interaction increases the affinity of AML1 for DNA. The CBFbeta/SMMHC fusion protein cooperates with AML1 to repress the transcription of AML1-regulated genes. We show that CBFbeta/SMMHC contains a repression domain in the C-terminal 163 amino acids of the SMMHC region that is required for inv(16)-mediated transcriptional repression. This minimal repression domain is sufficient for the association of CBFbeta/SMMHC with the mSin3A corepressor. In addition, the inv(16) fusion protein specifically associates with histone deacetylase 8 (HDAC8). inv(16) -mediated repression is sensitive to HDAC inhibitors. We propose a model whereby the inv(16) fusion protein associates with AML1 to convert AML1 into a constitutive transcriptional repressor.