mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets
mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets
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DOI：
10.1182/blood-2006-08-042192
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发表时间：
2007-03-01
期刊：
影响因子：
20.3
通讯作者：
Zimmerman, Guy A.
中科院分区：
文献类型：
--
作者：
Weyrich, Andrew S.;Denis, Melvin M.;Zimmerman, Guy A.
人类血小板的新活性不断出现。一个意想不到的反应是，在激活信号的作用下，由先前转录的RNA合成新的蛋白质。我们先前报道了活化的人血小板在哺乳动物雷帕霉素靶蛋白（mTOR）的翻译控制下合成B细胞淋巴瘤-3（Bcl-3）。mTOR信号通路在CD 34（+）干细胞衍生的巨核细胞中的个体发生和分布的表征现在证明它们将该调节系统转移到发育中的前血小板。我们还发现Bcl-3是活化血小板凝结纤维蛋白所必需的，证明了mTOR调节的蛋白质合成的功能意义。雷帕霉素对mTOR的抑制阻断了人血小板的凝块收缩。来自野生型小鼠的血小板响应于活化而合成Bcl-3，人血小板也是如此，来自Bcl-3靶向缺失的小鼠的血小板在血小板-纤维蛋白凝块中具有缺陷的纤维蛋白收缩，模拟用雷帕霉素处理人血小板。相反，Bcl-3在替代细胞系中的过表达增强了凝块收缩。这些研究确定了活化血小板中转录后基因调控和信号依赖性蛋白质合成的新特征，这些特征可能有助于血栓和伤口重塑，并表明转录后途径是血栓性疾病分子干预的靶点。
New activities of human platelets continue to emerge. One unexpected response is new synthesis of proteins from previously transcribed RNAs in response to activating signals. We previously reported that activated human platelets synthesize B-cell lymphoma-3 (Bcl-3) under translational control by mammalian target of rapamycin (mTOR). Characterization of the ontogeny and distribution of the mTOR signaling pathway in CD34(+) stem cell-derived megakaryocytes now demonstrates that they transfer this regulatory system to developing proplatelets. We also found that Bcl-3 is required for condensation of fibrin by activated platelets, demonstrating functional significance for mTOR-regulated synthesis of the protein. Inhibition of mTOR by rapamycin blocks clot retraction by human platelets. Platelets from wild-type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamycin. In contrast, overexpression of Bcl-3 in a surrogate cell line enhanced clot retraction. These studies identify new features of post-transcriptional gene regulation and signal-dependant protein synthesis in activated platelets that may contribute to thrombus and wound remodeling and suggest that posttranscriptional pathways are targets for molecular intervention in thrombotic disorders.