Cooperation of NF-κB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line
Cooperation of NF-κB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line
复制标题
DOI：
10.1128/jvi.00532-07
复制
发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Fujii, Masahiro
中科院分区：
文献类型：
--
作者：
Higuchi, Masaya;Tsubata, Chikako;Fujii, Masahiro
人类 T 细胞白血病病毒 1 型 (HTLV-1) 而不是 HTLV-2 与成人 T 细胞白血病相关，这两种密切相关的病毒的独特致病性被认为源于各自转化蛋白 HTLV-1 Tax1 和 HTLV-2 Tax2 的不同生物学功能。在这项研究中，我们证明 Tax1 而不是 Tax2 与 NF-kappa B2/p100 相互作用，并通过诱导 p100 裂解为活性转录因子 p52 来激活它。使用 RNA 干扰方法，我们进一步表明 NF-kappa B2/p100 是 Tax1 诱导的转化所必需的，这取决于 T 细胞系 (CTLL-2) 从白细胞介素 2 (IL-2) 依赖型生长转变为不依赖型生长的能力。虽然 Tax2 显示相对于 Tax1 而言降低的转化活性，但与仅存在于 Tax1 中的 PDZ 结构域结合基序 (PBM) 融合的 Tax2 在表达 p52 加工诱导剂的 CTLL-2 细胞中显示出与 Tax1 相当的转化活性。这些结果表明，NF-kappa B2/p100 的激活在 Tax1 介导的 T 细胞转化中起着至关重要的作用，并且 NF-kappa B2/p100 激活和 PBM 功能均导致 Tax1 相对于 Tax2 的转化活性增强，因此表明这些 Tax1 特异性功能在 HTLV-1 白血病发生中发挥着至关重要的作用。
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia, and the distinct pathogenicity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. In this study, we demonstrate that Tax1 but not Tax2 interacts with NF-kappa B2/p100 and activates it by inducing the cleavage of p100 into the active transcription factor p52. Using RNA interference methods, we further show that NF-kappa B2/p100 is required for the transformation induced by Tax1, as determined by the ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2)-dependent to -independent growth. While Tax2 shows a reduced transforming activity relative to Tax1, Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 shows transforming activity equivalent to that of Tax1 in CTLL-2 cells expressing an inducer of p52 processing. These results reveal that the activation of NF-kappa B2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF-kappa B2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2, thus suggesting that these Tax1-specific functions play crucial roles in HTLV-1 leukemogenesis.