Tax-independent constitutive IκB kinase activation in adult T-cell leukemia cells
Tax-independent constitutive IκB kinase activation in adult T-cell leukemia cells
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DOI：
10.1593/neo.03388
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发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Yamaoka, S
中科院分区：
文献类型：
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作者：
Hironaka, N;Mochida, K;Yamaoka, S
成人T细胞白血病（ATL）是一种致命的T细胞恶性肿瘤，在感染人类T细胞白血病病毒I型（HTLV-I）后很久才出现。我们以前报道过，核因子-κ B（NF-κ B）在ATL细胞中被组成性激活，尽管病毒蛋白的表达几乎检测不到，包括Tax，已知其持续激活NF-κ B。在这里，我们证明，ATL细胞，不表达可检测的Tax蛋白表现出组成型IkappaB激酶（IKK）的活动。转染研究显示，显性阴性形式的IKK 1，而不是IKK 2或NF-κ B必需调节剂（NEMO），抑制ATL细胞中的组成性NF-κ B活性。这种IKK活性伴随着p52表达的升高，表明最近描述的NF-κ B激活的非经典途径在ATL细胞中起作用。我们最终表明，在HTLV-1感染的T细胞中，IkappaB α的超阻遏物形式（SR-Ikappabetaalpha）对NF-κ B的特异性抑制导致细胞死亡，而不管Tax表达如何，这为NF-κ B在ATL细胞存活中的重要作用提供了明确的证据。总之，IKK复合物在ATL细胞中通过不同于Tax介导的IKK激活的细胞机制被组成性激活。进一步阐明这一细胞机制将有助于确立治疗ATL的基本原理。
Adult T-cell leukemia (ATL) is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I). We reported previously that nuclear factor-kappaB (NF-kappaB) was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-kappaB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IkappaB kinase (IKK) activity. Transfection studies revealed that a dominant-negative form of IKK1, and not of IKK2 or NF-kappaB essential modulator (NEMO), suppressed constitutive NF-kappaB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-kappaB activation operates in ATL cells. We finally show that specific inhibition of NF-kappaB by a super-repressor form of IkappaBalpha (SR-Ikappabetaalpha) in HTLV-I-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-kappaB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.