Human T-cell lymphotropic virus oncoprotein Tax represses TGF-β1 signaling in human T cells via c-Jun activation:: a potential mechanism of HTLV-I leukemogenesis
Human T-cell lymphotropic virus oncoprotein Tax represses TGF-β1 signaling in human T cells via c-Jun activation:: a potential mechanism of HTLV-I leukemogenesis
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DOI：
10.1182/blood-2001-12-0372
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发表时间：
2002-12-01
期刊：
影响因子：
20.3
通讯作者：
Hermine, O
中科院分区：
文献类型：
--
作者：
Arnulf, B;Villemain, A;Hermine, O
人T细胞白血病病毒I是成人T细胞白血病（ATL）的病原体，ATL是一种侵袭性T细胞恶性肿瘤。病毒癌蛋白Tax通过激活核因子κ B（NF-κ B）、CCAAT增强子结合蛋白（CREB）和活化蛋白-1（AP-1）途径，是T细胞稳态关键基因的转录调节因子。在ATL细胞中，活化的AP-1复合物诱导转化生长因子[31]（TGF-β 1）的产生。TGF-β 1是T细胞增殖和细胞毒性的抑制剂。在这里，我们表明，与正常的外周T细胞，ATL细胞是抵抗TGF-β 1诱导的生长抑制。外周T细胞中Tax蛋白的逆转录病毒转导导致TGF-β 1敏感性的丧失。Tax在HepG 2细胞中的瞬时转染以剂量依赖性方式特异性地抑制Smad/TGF-β 1信号传导。在Tax转染的存在下，增加Smad 3的量恢复了TGF-β 1信号传导。不能激活NF-κ B或CREB通路的Tax突变体也能够抑制Smad 3转录活性。接下来，我们已经证明Tax通过降低Smad 3 DNA结合活性来抑制TGF-β 1信号传导。然而，Tax并没有降低Smad 3的表达和核转位，也没有与Smad 3发生物理相互作用。相反，Tax诱导c-Jun N-末端激酶（JNK）活性和c-Jun磷酸化，导致Smad 3/c-Jun复合物的形成。尽管c-Jun单独消除了Smad 3 DNA结合，但Tax和显性阴性形式的JNK或c-Jun反义共转染恢复了Smad 3 DNA结合活性和TGF-β 1反应性。在ATL和Tax转导的正常T细胞中，c-Jun被组成性磷酸化。因此，我们描述了Tax的一种新功能，即通过JNK/c-Jun组成性激活作为TGF-β 1信号传导的抑制剂，这可能在ATL白血病发生中起关键作用。（血。2002; 100：4129-4138）（C）2002年由美国血液学会。
Human T-cell leukemia virus I is the etiologic agent of adult T-cell leukemia (ATL), an aggressive T-cell malignancy. The viral oncoprotein Tax, through the activation of nuclear factorKB (NF-kappaB), CCAAT-enhancer binding protein (CREB), and activated protein-1 (AP-1) pathways, is a transcriptional regulator of critical genes for T-cell homeostasis. In ATL cells, activated AP-1 complexes induce the production of transforming growth factor [31 (TGF-beta1). TGF-beta1 is an inhibitor of T-cell proliferation and cytotoxicity. Here we show that, in contrast to normal peripheral T cells, ATL cells are resistant to TGF-beta1-induced growth inhibition. The retroviral transduction of the Tax protein in peripheral T cells resulted in the loss of TGF-beta1 sensitivity. Transient transfection of Tax in HepG2 cells specifically inhibited Smad/TGF-beta1 signaling in a dose-dependent manner. In the presence of Tax transfection, increasing amounts of Smad3 restored TGF-beta1 signaling. Tax mutants unable to activate NF-KB or CREB pathways were also able to repress Smad3 transcriptional activity. Next we have demonstrated that Tax inhibits TGF-beta1 signaling by reducing the Smad3 DNA binding activity. However, Tax did not decrease the expression and the nuclear translocation of Smad3 nor did it interact physically with Smad3. Rather, Tax induced c-Jun N-terminal kinase (JNK) activity and c-Jun phosphorylation, leading to the formation of Smad3/c-Jun complexes. Whereas c-Jun alone abrogates Smad3 DNA binding, cotransfection of Tax and of a dominant-negative form of JNK or a c-Jun antisense-restored Smad3 DNA binding activity and TGF-[31 responsiveness. In ATL and in normal T cells transduced by Tax, c-Jun was constitutively phosphorylated. Thus, we describe a new function of Tax, as a repressor of TGF-[31 signaling through JNK/c-Jun constitutive activation, which may play a critical role in ATL leukemogenesis. (Blood. 2002; 100:4129-4138) (C) 2002 by The American Society of Hematology.