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Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor β singnaling

人 T 细胞白血病病毒 I 型癌蛋白 Tax 抑制 Smad 依赖性转化生长因子 β 信号传导

基本信息

批准号：
12670995
负责人：
MORI Naoki
金额：
$ 1.79万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670995/
关键词：
TGF-β HTLV-1 Tax HIV-1 Tat EBV LMP-1 Smad ATL p300 CBP NF-κB NF-κB HTLV-1 Tax

项目摘要

TGF-β is one of the best-characterized members of growth-inhibitory factors. Previously, it was reported that HTLV-I-infected T-cell clones were resistant to growth inhibition by TGF-β. HTLV-I Tax is a potent transcriptional regulator that can activate or repress specific cellular genes and that has been proposed to contribute to leukemogenesis in ATL. Therefore, we investigated whether Tax might block TGF-β signaling. Here it is shown that Tax can perturb Smad-dependent TGF-β signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a mutant Tax of transcription co-activators p300/CBP binding site, could not repress the Smad transactivation function. Overexpression of p300/CBP reversed Tax-mediated inhibition of Smad transactivation. These results suggest that Tax interferes with the recruitment of p300/CBP into transcription initiation complexes on TGF-β-responsive elements through its binding to p300/CBP. We also investigated whether HIV-1 Tat and EBV LMP-1 might block TGF-β signaling. Both proteins inhibit TGF-β-induced transactivation of the responsive promoters. Like Tax, Tat inhibits the ability of the Smads to mediate TGF-β-induced transcriptional activation by interfering with the recruitment of p300/CBP. On the contrary, LMP-1 can not interact with p300/CBP. C-terminal domain of LMP-1 is required for its repressive activity. Inhibition of Smad- dependent TGF-β-responsive promoter activation by LMP-1 is markedly restored by a constitutively active form of the κB inhibitory protein. LMP1 represses the TGF-β signaling through the NF-κB signaling pathway at the transcriptional level by competing for a limiting pool of p300/CBP. The novel function of Tax, Tat, and LMP-1 as repressors of TGF-β signaling may contribute to viral transformation.

转化生长因子-β是生长抑制因子中最具代表性的成员之一。此前，有报道称，感染HTLV-I的T细胞克隆对转化生长因子-β的生长抑制具有抵抗力。HTLV-I Tax是一种有效的转录调节因子，可以激活或抑制特定的细胞基因，已被认为与ATL的白血病发生有关。因此，我们研究了税收是否可以阻断转化生长因子-β信号转导通路。这表明，即使没有检测到Tax和Smad蛋白的直接相互作用，Tax也可以干扰Smad依赖的转化生长因子-β信号转导。重要的是，转录共激活因子p300/CBP结合位点的突变Tax不能抑制Smad反式激活功能。P300/CBP的过表达逆转了税收对Smad反式激活的抑制作用。这些结果表明，Tax通过与p300/CBP结合来干扰p300/CBP在转化生长因子-β反应元件上的转录起始复合体中的募集。我们还研究了HIV-1Tat和EBVLMP-1是否可以阻断转化生长因子-β信号转导。这两种蛋白都能抑制转化生长因子-β诱导的反应启动子的反式激活。和TAX一样，TAT通过干扰p300/CBP的募集，抑制Smads介导转化生长因子-β诱导的转录激活的能力。相反，LMP-1不能与p300/CBP相互作用。LMP-1的C末端结构域是其抑制活性所必需的。LMP-1对Smad依赖的转化生长因子-β反应性启动子激活的抑制作用可通过κB抑制蛋白的结构活性形式显著恢复。LMP1通过竞争p300/β的限制池，在转录水平上通过NF-κB信号通路抑制转化生长因子-CBP信号传导。Tax、Tat和LMP-1作为转化生长因子-β信号抑制因子的新功能可能有助于病毒转化。