Activation of NF-kappaB by HTLV-I and implications for cell transformation.
Activation of NF-kappaB by HTLV-I and implications for cell transformation.
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作者：
Shao-Cong Sun;S. Yamaoka
人类 T 细胞白血病病毒 I 型 (HTLV-I) 引起的 T 细胞转化涉及细胞转录因子（包括 NF-kappaB 家族成员）的失调。在正常 T 细胞中，NF-κB 激活会短暂发生以响应免疫刺激，这是抗原刺激的 T 细胞增殖和存活所必需的。然而，HTLV-I 会诱导 NF-κB 的持续激活，导致大量细胞基因的表达失调，进而有助于诱导 T 细胞转化。 HTLV-I 转化蛋白 Tax 充当 IkappaB 激酶 (IKK) 的细胞内刺激剂，IKK 是一种通过多种刺激介导 NF-kappaB 激活的细胞激酶。 Tax 与 IKK 发生物理相互作用，并使这种诱导型激酶持续活跃。通过组装不同的 Tax/IKK 复合物，Tax 的目标是经典和非经典 NF-kappaB 信号通路的持续激活。虽然 Tax 在 HTLV-I 介导的 NF-kappaB 激活中发挥主要作用，但最近的研究表明，IKK/NF-kappaB 信号通路在新鲜分离的成体 T 细胞白血病 (ATL) 细胞中也被激活，这些细胞通常缺乏可检测到的 Tax 表达。这种 NF-kappaB 激活的税独立途径的潜在机制仍然知之甚少。阐明 ATL 细胞中 NF-kappaB 组成型激活的确切性质和后果对于制定针对这种 T 细胞恶性肿瘤的合理治疗策略非常重要。
T-cell transformation by the human T-cell leukemia virus type I (HTLV-I) involves deregulation of cellular transcription factors, including members of the NF-kappaB family. In normal T cells, NF-kappaB activation occurs transiently in response to immune stimuli, which is required for antigen-stimulated T-cell proliferation and survival. However, HTLV-I induces persistent activation of NF-kappaB, causing deregulated expression of a large array of cellular genes, which in turn contributes to the induction of T-cell transformation. The HTLV-I transforming protein Tax functions as an intracellular stimulator of IkappaB kinase (IKK), a cellular kinase mediating NF-kappaB activation by diverse stimuli. Tax physically interacts with IKK and renders this inducible kinase constitutively active. By assembling different Tax/IKK complexes, Tax targets the persistent activation of both canonical and noncanonical NF-kappaB signaling pathways. Whereas Tax plays a primary role in HTLV-I-mediated NF-kappaB activation, recent studies reveal that the IKK/NF-kappaB signaling pathway is also activated in freshly isolated adult T-cell leukemia (ATL) cells that often lack detectable Tax expression. The mechanism underlying this Tax-independent pathway of NF-kappaB activation remains poorly understood. Clarifying the precise nature and consequences of the constitutive NF-kappaB activation in ATL cells is important for developing rational therapeutic strategies for this T-cell malignancy.