Abstract：
Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Mutational analysis has demonstrated that the tumor suppressor, F-box and WD repeat domain containing 7 (FBXW7/FBW7/CDC4), is mutated in primary ATL patients. However, even in the absence of genetic mutations, FBXW7 substrates are stabilized in ATL cells, suggesting additional mechanisms can prevent FBXW7 functions. Here, we report that the viral oncoprotein Tax represses FBXW7 activity, resulting in the stabilization of activated Notch intracellular domain, c-MYC, Cyclin E, and myeloid cell leukemia sequence 1 (BCL2-related) (Mcl-1). Mechanistically, we demonstrate that Tax directly binds to FBXW7 in the nucleus, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 substrates. In support of the nuclear role of Tax, a non-degradable form of the nuclear factor kappa B subunit 2 (NFκB2/p100) was found to delocalize Tax to the cytoplasm, thereby preventing Tax interactions with FBXW7 and Tax-mediated inhibition of FBXW7. Finally, we characterize a Tax mutant that is unable to interact with FBXW7, unable to block FBXW7 tumor suppressor functions, and unable to effectively transform fibroblasts. These results demonstrate that HTLV-I Tax can inhibit FBXW7 functions without genetic mutations to promote an oncogenic state. These results suggest that Tax-mediated inhibition of FBXW7 is likely critical during the early stages of the cellular transformation process.
OBJECTIVE: F-box and WD repeat domain containing 7 (FBXW7), a critical tumor suppressor of human cancers, is frequently mutated or epigenetically suppressed. Loss of FBXW7 functions is associated with stabilization and increased expression of oncogenic factors such as Cyclin E, c-Myc, Mcl-1, mTOR, Jun, and Notch. In this study, we demonstrate that the human retrovirus human T-cell leukemia virus type 1 oncoprotein Tax directly interacts with FBXW7, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 cellular substrates. We further demonstrate that a Tax mutant unable to interact with and inactivate FBXW7 loses its ability to transform primary fibroblasts. Collectively, our results describe a novel mechanism used by a human tumor virus to promote cellular transformation.
OBJECTIVE: F-box and WD repeat domain containing 7 (FBXW7), a critical tumor suppressor of human cancers, is frequently mutated or epigenetically suppressed. Loss of FBXW7 functions is associated with stabilization and increased expression of oncogenic factors such as Cyclin E, c-Myc, Mcl-1, mTOR, Jun, and Notch. In this study, we demonstrate that the human retrovirus human T-cell leukemia virus type 1 oncoprotein Tax directly interacts with FBXW7, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 cellular substrates. We further demonstrate that a Tax mutant unable to interact with and inactivate FBXW7 loses its ability to transform primary fibroblasts. Collectively, our results describe a novel mechanism used by a human tumor virus to promote cellular transformation.
摘要：
人T细胞白血病病毒1型（HTLV-I）是成人T细胞白血病（ATL）的病原体。突变分析表明，肿瘤抑制因子，F-box和WD重复结构域含有7（FBXW7/FBW7/CDC4），在原发性ATL患者中突变。然而,即使没有基因突变，FBXW7底物在ATL细胞中稳定，建议额外的机制可以阻止FBXW7功能。这里,我们报告说，病毒癌蛋白税抑制FBXW7的活性，导致激活的Notch细胞内结构域的稳定，c-MYC,细胞周期蛋白E,和髓样细胞白血病序列1(BCL2相关)(Mcl-1)。机械上,我们证明了税收在原子核中直接与FBXW7结合，与FBXW7的结合有效竞争其他靶标，导致FBXW7底物的泛素化和降解减少。为了支持税收的核作用，发现核因子κB亚基2（NFκB2/p100）的不可降解形式可将Tax离域到细胞质中，从而防止税收与FBXW7的相互作用和税收介导的FBXW7抑制。最后,我们描述了一个不能与FBXW7相互作用，不能阻断FBXW7肿瘤抑制功能的Tax突变体，无法有效转化成纤维细胞。这些结果表明，HTLV-ITax可以抑制FBXW7功能，而不会发生基因突变以促进致癌状态。这些结果表明，在细胞转化过程的早期阶段，Tax介导的FBXW7抑制可能至关重要。
目的：F-box和WD重复结构域含有7（FBXW7），人类癌症的关键肿瘤抑制剂，经常发生突变或表观遗传抑制。FBXW7功能的丧失与致癌因子如CyclinE的稳定和表达增加有关,c-Myc,Mcl-1mTOR,Jun,还有Notch.在这项研究中,我们证明,人类逆转录病毒人类T细胞白血病病毒1型癌蛋白Tax与FBXW7直接相互作用,有效地超越了与FBXW7结合的其他靶标,导致FBXW7细胞底物的泛素化和降解减少.我们进一步证明，无法与FBXW7相互作用并使其失活的Tax突变体失去了转化原代成纤维细胞的能力。总的来说，我们的结果描述了人类肿瘤病毒促进细胞转化的新机制。
目的：F-box和WD重复结构域含有7（FBXW7），人类癌症的关键肿瘤抑制剂，经常发生突变或表观遗传抑制。FBXW7功能的丧失与致癌因子如CyclinE的稳定和表达增加有关,c-Myc,Mcl-1mTOR,Jun,还有Notch.在这项研究中,我们证明,人类逆转录病毒人类T细胞白血病病毒1型癌蛋白Tax与FBXW7直接相互作用,有效地超越了与FBXW7结合的其他靶标,导致FBXW7细胞底物的泛素化和降解减少.我们进一步证明，无法与FBXW7相互作用并使其失活的Tax突变体失去了转化原代成纤维细胞的能力。总的来说，我们的结果描述了人类肿瘤病毒促进细胞转化的新机制。
