Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-β signaling by blocking the association of smad proteins with smad-binding element
Human T-cell lymphotropic virus type 1 tax inhibits transforming growth factor-β signaling by blocking the association of smad proteins with smad-binding element
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DOI：
10.1074/jbc.m200150200
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发表时间：
2002-09-13
影响因子：
4.8
通讯作者：
Kim, SJ
中科院分区：
文献类型：
--
作者：
Lee, DK;Kim, BC;Kim, SJ
人类T细胞嗜淋巴细胞病毒I型（HTLV-1）癌蛋白Tax与HTLV-1感染相关的各种临床表现有关，包括侵袭性和致命性T细胞恶性肿瘤。由于许多人类HTLV-1感染的T细胞系对转化生长因子β（TGF-β）的生长抑制活性具有抗性，我们研究了HTVL-1-Tax癌蛋白调节TGF-β信号传导的可能性。我们表明，税收显着降低转录活性和生长抑制响应TGF-β。Tax抑制TGF-β诱导的纤溶酶原激活物抑制剂-1表达和Smad 2磷酸化。竞争性相互作用研究表明，Tax部分通过破坏Smads与转录辅激活因子p300的相互作用来抑制TGF-β信号传导。Tax直接与Smad 2、Smad 3和Smad 4相互作用; Smad MH 2结构域与Tax结合。此外，Tax抑制Smad3.Smad4复合物的形成及其与DNA的结合。这些结果表明Tax对Smad介导的信号传导的抑制可能有助于HTLV-1相关的白血病发生。
The human T-cell lymphotropic virus type I (HTLV-1) oncoprotein Tax is implicated in various clinical manifestations associated with infection by HTLV-1, including an aggressive and fatal T-cell malignancy. Because many human HTLV-1-infected T-cell lines are resistant to the growth inhibitory activity of transforming growth factor beta (TGF-beta), we examined the possibility that the HTVL-1-Tax oncoprotein regulates TGF-beta signaling. We show that Tax significantly decreases transcriptional activity and growth inhibition in response to TGF-beta. Tax inhibits TGF-beta-induced plasminogen activator inhibitor-1 expression and Smad2 phosphorylation. Competitive interaction studies show that Tax inhibits TGF-beta signaling, in part, by disrupting the interaction of the Smads with the transcriptional co-activator p300. Tax directly interacts with Smad2, Smad3, and Smad4; the Smad MH2 domain binds to Tax. Furthermore, Tax inhibits Smad3.Smad4 complex formation and its DNA binding. These results suggest that suppression of Smad-mediated signaling by Tax may contribute to HTLV-1-associated leukemogenesis.