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

TGF-β是生长抑制因子中最具特征的成员之一。先前有报道htlv -i感染的t细胞克隆对TGF-β的生长抑制具有抗性。HTLV-I Tax是一种有效的转录调节剂，可以激活或抑制特定的细胞基因，并被认为有助于ATL的白血病发生。因此，我们研究了税收是否可能阻断TGF-β信号传导。本研究表明，即使没有检测到Tax和Smad蛋白的直接相互作用，但Tax可以干扰Smad依赖性TGF-β信号传导。重要的是，转录共激活因子p300/CBP结合位点的突变体税收不能抑制Smad的交易功能。p300/CBP的过表达逆转了税收介导的Smad交易激活抑制。这些结果表明，通过与p300/CBP的结合，Tax干扰了p300/CBP在TGF-β响应元件上转录起始复合物的募集。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。两种蛋白均抑制TGF-β诱导的应答启动子的转激活。与Tax一样，Tat通过干扰p300/CBP的募集，抑制Smads介导TGF-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端结构域是其抑制活性所必需的。LMP-1对Smad依赖性TGF-β响应启动子激活的抑制作用通过组成型活性的κB抑制蛋白明显恢复。LMP1通过NF-κB信号通路在转录水平上通过竞争p300/CBP限制池抑制TGF-β信号。Tax， Tat和LMP-1作为TGF-β信号抑制因子的新功能可能有助于病毒转化。

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.