PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation
PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation
复制标题
DOI：
10.1182/blood-2008-10-185660
复制
发表时间：
2009-04-30
期刊：
影响因子：
20.3
通讯作者：
Xiao, Gutian
中科院分区：
文献类型：
--
作者：
Yan, Pengrong;Fu, Jing;Xiao, Gutian
人类T细胞白血病病毒I型(HTLV-I)Tax癌蛋白解除细胞致癌信号调控的机制已被广泛研究，但Tax本身是如何调控的在很大程度上仍不清楚。在这里，我们报告了税收被PDLIM2负调控，它促进了税收K48连接的多泛素化。此外，PDLIM2从其功能部位将Tax招募到核基质中，在那里多泛素化的Tax被蛋白酶体降解。在体外和动物体内，PDLIM2一致地抑制了Tax介导的信号激活、细胞转化和肿瘤发生。值得注意的是，在HTLV-I转化的T细胞中，PDLIM2的表达下调，PDLIM2重组逆转了恶性细胞的致瘤性。这些研究表明，HTLV-I/TAX和PDLIM2之间的平衡可能决定了HTLV-I感染的结局。这些研究还提出了一种潜在的治疗策略，用于治疗与HTLV-I感染和/或PDLIM2去调控相关的癌症和其他疾病。(血。2009；113：4370-4380)
The mechanisms by which the human T-cell leukemia virus type I (HTLV-I) Tax oncoprotein deregulates cellular signaling for oncogenesis have been extensively studied, but how Tax itself is regulated remains largely unknown. Here we report that Tax was negatively regulated by PDLIM2, which promoted Tax K48-linked polyubiquitination. In addition, PDLIM2 recruited Tax from its functional sites into the nuclear matrix where the polyubiquitinated Tax was degraded by the proteasome. Consistently, PDLIM2 suppressed Tax-mediated signaling activation, cell transformation, and oncogenesis both in vitro and in animal. Notably, PDLIM2 expression was down-regulated in HTLV-I-transformed T cells, and PDLIM2 reconstitution reversed the tumorigenicity of the malignant cells. These studies indicate that the counterbalance between HTLV-I/Tax and PDLIM2 may determine the outcome of HTLV-I infection. These studies also suggest a potential therapeutic strategy for cancers and other diseases associated with HTLV-I infection and/or PDLIM2 deregulation. (Blood. 2009; 113: 4370-4380)