Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis.
Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis.
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DOI：
10.1038/onc.2010.374
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发表时间：
2010-12-09
期刊：
影响因子：
8
通讯作者：
Xiao, G.
中科院分区：
文献类型：
--
作者：
Fu, J.;Yan, P.;Li, S.;Qu, Z.;Xiao, G.
人类T细胞白血病病毒I型（HTLV-I）编码一种Tax癌蛋白，在病毒复制和细胞转化中起关键作用。我们最近的研究表明，HTLV-I/Tax和PDZ-LIM结构域蛋白PDLIM 2之间的平衡可能决定HTLV-I感染的结果。尽管HTLV-I在表观遗传学上特别是在转化细胞中抑制PDLIM 2，但PDLIM 2将Tax穿梭到核基质中进行遍在化介导的蛋白酶体降解，从而抑制HTLV-I的转化能力。在这里，我们进一步表明PDLIM 2直接与Tax结合，这是由PDLIM 2在氨基酸236-254处的推定α-螺旋基序介导的。然而，选择性破坏这种短螺旋削弱了PDLIM 2关闭Tax与核基质的泛素化介导的降解，因此，PDLIM 2失去了抑制肿瘤的能力。虽然PDLIM 2的C-末端LIM结构域不是Tax结合所必需的，但PDLIM 2与核基质相互作用是重要的。因此，LIM结构域对于PDLIM 2介导的Tax抑制是必需的。相反，PDLIM 2的N-末端PDZ结构域对于所有这些事件都是不稳定的，尽管PDZ结构域参与PDLIM 2与细胞骨架的结合。这些研究剖析了PDLIM 2内的功能序列及其在税收调控中的独特作用。
Human T-cell leukemia virus type I (HTLV-I) encodes a Tax oncoprotein that has crucial roles in both virus replication and cell transformation. Our recent studies suggest that the counterbalance between HTLV-I/Tax and PDZ-LIM domain-containing protein PDLIM2 may determine the outcome of HTLV-I infection. Although HTLV-I represses PDLIM2 epigenetically and specifically in transformed cells, PDLIM2 shuttles Tax into the nuclear matrix for ubiquitination-mediated proteasomal degradation, thereby suppressing the transforming ability of HTLV-I. Here, we have further shown that PDLIM2 binds to Tax directly, which was mediated by a putative α-helix motif of PDLIM2 at amino acids 236–254. Consistently, selective disruption of this short-helix crippled PDLIM2 in shutting Tax to the nuclear matrix for ubiquitination-mediated degradation, therefore, PDLIM2 lost the ability in tumor suppression. Although the C-terminal LIM domain of PDLIM2 was not required for Tax binding, it was important for PDLIM2 to interact with the nuclear matrix. Accordingly, the LIM domain was essential for PDLIM2-mediated Tax repression. On the contrary, the N-terminal PDZ domain of PDLIM2 was dispensable for all these events, although the PDZ domain was involved in PDLIM2 binding to cytoskeleton. These studies dissect functional sequences within PDLIM2 and their distinct roles in Tax regulation.
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影响因子：
8
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.92.4.1057
发表时间：
1995-02-14
影响因子：
11.1
作者：
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通讯作者：
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