Sun Shao-Cong, Yamaoka Shoji
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA.
Oncogene. 2005 Sep 5;24(39):5952-64. doi: 10.1038/sj.onc.1208969.
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.
I型人类T细胞白血病病毒（HTLV-I）引起的T细胞转化涉及细胞转录因子的失调，包括核因子κB（NF-κB）家族成员。在正常T细胞中，NF-κB的激活在免疫刺激下短暂发生，这是抗原刺激的T细胞增殖和存活所必需的。然而，HTLV-I诱导NF-κB的持续激活，导致大量细胞基因的表达失调，进而促成T细胞转化的诱导。HTLV-I转化蛋白Tax作为IkB激酶（IKK）的细胞内刺激物发挥作用，IKK是一种通过多种刺激介导NF-κB激活的细胞激酶。Tax与IKK发生物理相互作用，使这种可诱导激酶持续激活。通过组装不同的Tax/IKK复合物，Tax靶向经典和非经典NF-κB信号通路的持续激活。虽然Tax在HTLV-I介导的NF-κB激活中起主要作用，但最近的研究表明，在通常缺乏可检测到的Tax表达的新鲜分离的成人T细胞白血病（ATL）细胞中，IKK/NF-κB信号通路也被激活。这种不依赖Tax的NF-κB激活途径的潜在机制仍知之甚少。阐明ATL细胞中组成型NF-κB激活的确切性质和后果对于开发针对这种T细胞恶性肿瘤的合理治疗策略很重要。
