Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms
Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms
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DOI：
10.1074/jbc.m110465200
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发表时间：
2002-05-17
影响因子：
4.8
通讯作者：
Blackwell, TK
中科院分区：
文献类型：
--
作者：
Johnson, BA;Stehn, JR;Blackwell, TK
立即早期基因tristetraprolin（TTP）在许多细胞类型中由许多细胞外刺激瞬时诱导。TTP编码锌指蛋白，其可以结合编码肿瘤坏死因子-α（TNF α）和其它细胞因子的mRNA并使其不稳定。我们假设TTP在生长因子反应途径中也有更广泛的作用。为了支持该模型，我们先前已经确定TTP通过线粒体途径诱导细胞凋亡，类似于某些致癌基因和其他立即早期基因，并且TTP使细胞对TNF α的促细胞凋亡信号敏感。在这项研究中，我们表明，TTP和相关的蛋白质TIS 11b和TIS 11 d特异性结合14-3-3蛋白和个别14-3-3亚型优先结合不同的磷酸化TTP物种。14-3-3结合似乎并不抑制或促进TTP诱导的细胞凋亡，而是将TTP定位于细胞质的多种机制之一。我们的研究结果提供了14-3-3与RNA结合蛋白功能性相互作用并在体内与11型14-3-3结合位点结合的第一个例子。他们还表明，14-3-3结合是调节TTP功能的刺激和相互作用的复杂网络的一部分。
The immediate early gene tristetraprolin (TTP) is induced transiently in many cell types by numerous extracellular stimuli TTP encodes a zinc finger protein that can bind and destabilize mRNAs that encode tumor necrosis factor-alpha (TNFalpha) and other cytokines. We hypothesize that TTP also has a broader role in growth factor-responsive pathways. In support of this model, we have previously determined that TTP induces apoptosis through the mitochondrial pathway, analogously to certain oncogenes and other immediate-early genes, and that TTP sensitizes cells to the pro-apoptotic signals of TNFa. In this study, we show that TTP and the related proteins TIS11b and TIS11d bind specifically to 14-3-3 proteins and that individual 14-3-3 isoforms preferentially bind to different phosphorylated TTP species. 14-3-3 binding does not appear to inhibit or promote induction of apoptosis by TTP but is one of multiple mechanisms that localize TTP to the cytoplasm. Our results provide the first example of 14-3-3 interacting functionally with an RNA binding protein and binding in vivo to a Type 11 14-3-3 binding site. They also suggest that 14-3-3 binding is part of a complex network of stimuli and interactions that regulate TTP function.