The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1
The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1
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DOI：
10.1128/mcb.24.3.1033-1043.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Hirai, H
中科院分区：
文献类型：
--
作者：
Imai, Y;Kurokawa, M;Hirai, H
AML1(RUNX1)基因是人类白血病最常见的易位靶点之一，编码一种DNA结合蛋白，通过转录调控多种基因在髓系分化中发挥关键作用。此前，我们报道了AML1在两个丝氨酸残基上被磷酸化，依赖于细胞外信号调节激酶的激活，从而正向调节AML1的转录活性。在这里，我们证明了AML1与辅阻遏子mSin3A之间的相互作用是由AML1的磷酸化来调节的，并且由磷酸化诱导的AML1从mSin3A中释放出来激活了它的转录活性。此外，AML1的磷酸化调节其在核内的位置，并破坏AML1与mSin3A在核基质中的共存。研究表明，AML1的异二聚体伙伴PEBP2beta/CBFbeta在保护AML1免受蛋白酶体介导的降解方面起到了作用。我们发现mSin3A也保护AML1免受蛋白酶体介导的降解，并且磷酸化诱导的AML1从mSin3A中释放导致AML1以时间依赖的方式降解。本研究通过蛋白质修饰和与辅因子的相互作用为转录因子的功能调控提供了一种新的机制。
The AML1 (RUNX1) gene, one of the most frequent targets of translocations associated with human leukemias, encodes a DNA-binding protein that plays pivotal roles in myeloid differentiation through transcriptional regulation of various genes. Previously, we reported that AML1 is phosphorylated on two serine residues with dependence on activation of extracellular signal-regulated kinase, which positively regulates the transcriptional activity of AML1 Here, we demonstrate that the interaction between AML1 and the corepressor mSin3A is regulated by phosphorylation of AML1 and that release of AML1 from mSin3A induced by phosphorylation activates its transcriptional activity. Furthermore, phosphorylation of AML1 regulates its intranuclear location and disrupts colocalization of AML1 with mSin3A in the nuclear matrix. PEBP2beta/CBFbeta, a heterodimeric partner of AML1, was shown to play a role in protecting AML1 from proteasome-mediated degradation. We show that mSin3A also protects AML1 from proteasome-mediated degradation and that phosphorylation-induced release of AML1 from mSin3A results in degradation of AML1 in a time-dependent manner. This study provides a novel regulatory mechanism for the function of transcription factors mediated by protein modification and interaction with cofactors.