P300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein
P300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein
复制标题
DOI：
10.1038/sj.onc.1202889
复制
发表时间：
1999-09-02
期刊：
影响因子：
8
通讯作者：
Brandt, SJ
中科院分区：
文献类型：
--
作者：
Huang, SM;Qiu, Y;Brandt, SJ
TALI（或SCL）基因的激活最初通过其参与复发性染色体易位而被鉴定，是T细胞急性淋巴细胞白血病（T-ALL）中最常见的功能获得性突变。TAL 1蛋白含有一个大家族转录因子特有的碱性螺旋-环-螺旋（bHLH）基序，该基序控制从E盒靶元件转录，作为具有E2 A和HEB编码基因产物的异二聚体。小鼠基因敲除研究表明，这种转录因子是胚胎和成人造血所必需的，大量证据表明它在终末红细胞分化中具有特异性功能。我们研究了广泛表达的核蛋白p300是否也与TAL 1相互作用，p300已知作为参与细胞分化的其他bHLH蛋白的共激活剂，在用二甲基亚砜（DMSO）诱导分化的小鼠红白血病（MEL）细胞的提取物中发现p300与TAL 1共免疫沉淀，p300和Tal 1在分化中的MEL细胞提取物中共同的E盒DNA结合复合物中观察到。p300在蛋白质下拉试验中也与Tal 1相互作用，表明这是一种直接相互作用。最后，p300增强转录Tal 1从一个E盒含有启动子和GAL 4-Tal 1融合从一个启动子含有GAL 4 DNA结合元件。缺失分析确定的bHLH结构域的Tall和氨基末端序列的p300作为必要的p300刺激的反式激活和Tal 1-p300在体外的相互作用。这些结果表明，转录辅激活因子p300的募集可以正向调节TAL 1指导的基因表达。它们在MEL细胞中的相互作用依赖于分化诱导剂的加入，进一步表明，这种TAL 1-p300完全可能在终末红细胞分化中具有重要作用。
Activation of the TALI (or SCL) gene, originally identified through its involvement by a recurrent chromosomal translocation, is the most frequent gain-of-function mutation recognized in T-cell acute lymphoblastic leukemia (T-ALL). The TAL1 proteins contain a basic helix-loop-helix (bHLH) motif characteristic of a large family of transcription factors that control transcription from an E box target element as heterodimers with the E2A- and HEB-encoded gene products. Gene knockout studies in mice indicate that this transcription factor is required for embryonic and adult hematopoiesis, and considerable evidence suggests it has specific functions in terminal erythroid differentiation. We investigated whether the broadly expressed nuclear protein p300, known to function as a coactivator for other bHLH proteins involved in cellular differentiation, also interacts with TAL1, p300 was found to coimmunoprecipitate with Tal1 in extracts from murine erythroleukemia (MEL) cells induced to differentiate with dimethylsulfoxide (DMSO), and p300 and Tal1 were observed in a common E box DNA-binding complex in extracts from differentiating MEL cells. p300 also interacted with Tal1 in protein pulldown assays, suggesting this was a direct interaction. Finally, p300 augmented transcription by Tal1 from an E box-containing promoter and by a GAL4-Tal1 fusion from a promoter containing the GAL4 DNA-binding element. Deletion analysis identified the bHLH domain of Tall and amino-terminal sequences of p300 as necessary for p300-stimulated transactivation and Tal1-p300 interaction in vitro. These results indicate that recruitment of the transcriptional coactivator p300 can positively regulate TAL1-directed gene expression. The dependence of their interaction in MEL cells on addition of a differentiation inducer suggests, further, that this TAL1-p300 complete may have an important role in terminal erythroid differentiation.