HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells
HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells
复制标题
DOI：
10.1073/pnas.0507631103
复制
发表时间：
2006-01-17
影响因子：
11.1
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Satou, Y;Yasunaga, J;Matsuoka, M
人T细胞白血病病毒I型（HTLV-1）在长潜伏期后在2-5%的携带者中引起成人T细胞白血病（ATL）。HTLV-I编码的蛋白Tax诱导增殖并抑制凋亡，导致感染细胞的克隆增殖。然而，ATL细胞中的tax基因表达被几种机制破坏，包括tax基因的遗传变化和5'长末端重复序列（LTR）的DNA甲基化/缺失。由于Tax是体内细胞毒性T淋巴细胞的主要靶标，Tax表达的丧失应使ATL细胞能够逃避宿主免疫系统。在ATL细胞中，HTLV-1的5' LTR经常被高甲基化或缺失，而3' LTR保持未甲基化和完整，表明3' LTR参与白血病发生。在这里，我们表明，由HTLV-1前病毒基因组的负链编码的基因，HTLV-1碱性亮氨酸拉链因子（HBZ），在所有ATL细胞中从3 '-LTR转录。通过短干扰RNA抑制HBZ基因转录抑制ATL细胞增殖。此外，HBZ基因表达促进人T细胞系的增殖。用突变的HBZ基因转染的T细胞系的分析表明，HBZ以其RNA形式促进T细胞增殖，而HBZ蛋白通过5' LTR抑制Tax介导的病毒转录。因此，单个HBZ基因在两种不同的分子形式中具有双峰功能。HBZ RNA的促生长活性可能在HTLV-1的肿瘤发生中起重要作用。
Human T cell leukemia virus type I (HTLV-1) causes adult T cell leukemia (ATL) in 2-5% of carriers after a long latent period. An HTLV-I encoded protein, Tax, induces proliferation and inhibits apoptosis, resulting in clonal proliferation of infected cells. However, tax gene expression in ATL cells is disrupted by several mechanisms, including genetic changes in the tax gene and DNA methylation/deletion of the 5' long terminal repeat (LTR). Because Tax is the major target of cytotoxic T-lymphocytes in vivo, loss of Tax expression should enable ATL cells to escape the host immune system. The 5' LTR of HTLV-I is frequently hypermethylated or deleted in ATL cells, whereas the 3' LTR remains unmethylated and intact, suggesting the involvement of the 3' LTR in leukemogenesis. Here we show that a gene encoded by the minus strand of the HTLV-I proviral genome, HTLV-1 basic leucine zipper factor (HBZ), is transcribed from 3'-LTR in all ATL cells. Suppression of HBZ gene transcription by short interfering RNA inhibits proliferation of ATL cells. In addition, HBZ gene expression promotes proliferation of a human T cell line. Analyses of T cell lines transfected with mutated HBZ genes showed that HBZ promotes T cell proliferation in its RNA form, whereas HBZ protein suppresses Tax-mediated viral transcription through the 5' LTR. Thus, the single HBZ gene has bimodal functions in two different molecular forms. The growth-promoting activity of HBZ RNA likely plays an important role in oncogenesis by HTLV-1.