The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis.
The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis.
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DOI：
10.1186/ar1441
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发表时间：
2004
影响因子：
4.9
通讯作者：
Blackshear PJ
中科院分区：
文献类型：
--
作者：
Carrick DM;Lai WS;Blackshear PJ
Tristetraprolin（TTP）是人类三种蛋白质小家族中研究最充分的成员，其特征在于具有高度保守序列和间隔的串联CCCH锌指（TZF）结构域。虽然最初发现TTP是一种可以通过用生长因子和有丝分裂原刺激成纤维细胞而快速和瞬时诱导的基因，但现在已知TTP可以结合mRNA中富含AU的元件，导致从该mRNA中去除poly（A）尾并增加mRNA周转率。这种活性是在建立TTP缺陷小鼠后发现的，并发现其具有全身性炎症综合征，伴有严重的多关节关节炎和自身免疫，以及髓和髓外骨髓增生。该综合征似乎主要是由于过量的循环肿瘤坏死因子-α（TNF-α），这是由于TNF-α mRNA的稳定性增加和随后细胞因子分泌速率升高所致。骨髓增生可能部分是由于粒细胞-巨噬细胞集落刺激因子（GM-CSF）的稳定性增加。本文简要介绍了小鼠TTP缺乏综合征的特点及其可能的遗传修饰因素，以及TNF-α和GM-CSF mRNA中TTP结合位点的特点。最近的结构数据之间的复合物的特点，RNA和TTP相关的蛋白质之一进行了审查，并用于模拟TTP-RNA结合复合物。我们回顾了目前的知识TTP序列变异在人类和讨论可能的贡献TTP相关蛋白在小鼠生理和人类单核细胞。TNF-α和GM-CSF mRNA降解的TTP途径是类风湿性关节炎抗TNF-α治疗的一个可能的新靶点，也适用于已证实对抗TNF-α治疗有反应的其他疾病。
Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-α (TNF-α), resulting from the increased stability of the TNF-α mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte–macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-α and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-α and GM-CSF mRNA degradation is a possible novel target for anti-TNF-α therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-α therapy.
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影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G
影响因子：
4.8
作者：
Johnson, BA;Stehn, JR;Blackwell, TK
通讯作者：
Blackwell, TK
影响因子：
4.8
作者：
Lai, WS;Carballo, E;Blackshear, PJ
通讯作者：
Blackshear, PJ
影响因子：
0.9
作者：
Feldman, M;Taylor, P;Maini, RN
通讯作者：
Maini, RN