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.

TGF-β 是生长抑制因子中最有特征的成员之一，此前有报道称，HTLV-I 感染的 T 细胞克隆对 TGF-β 的生长抑制具有抵抗力，HTLV-I Tax 是一种有效的转录因子。可以激活或抑制特定细胞基因，并且已被认为有助于 ATL 中的白血病发生，因此，我们研究了 Tax 是否可能阻断 TGF-β 信号传导。尽管没有检测到 Tax 和 Smad 蛋白的直接相互作用，但 Smad 依赖性 TGF-β 信号转导仍然存在。重要的是，转录共激活剂 p300/CBP 结合位点的突变 Tax 不能抑制 p300/CBP 的 Smad 反式激活功能。逆转 Tax 介导的 Smad 反式激活抑制。这些结果表明，Tax 通过其干扰 p300/CBP 招募到 TGF-β 响应元件上的转录起始复合物中。我们还研究了 HIV-1 Tat 和 EBV LMP-1 是否可能阻断 TGF-β 信号传导，与 Tax 一样，Tat 也抑制 Smad 的能力。通过干扰 p300/CBP 的募集来介导 TGF-β 诱导的转录激活，相反，LMP-1 不能与 p300/CBP 相互作用。 LMP-1 结构域是其抑制活性所必需的。LMP-1 对 Smad 依赖性 TGF-β 反应性启动子的抑制可通过 κB 抑制蛋白的组成型活性形式显着恢复，从而抑制 TGF-β 信号转导。通过竞争 p300/CBP 的限制池，在转录水平上调节 NF-κB 信号通路 Tax、Tat 和 LMP-1 的新功能。 TGF-β信号传导阻遏物可能有助于病毒转化。