The active component of ginseng, ginsenoside Rb1, improves erythropoiesis in models of Diamond-Blackfan anemia by targeting Nemo-like kinase.
The active component of ginseng, ginsenoside Rb1, improves erythropoiesis in models of Diamond-Blackfan anemia by targeting Nemo-like kinase.
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人参的活性成分Rb 1通过靶向Nemo样激酶改善Diamond-Blackfan贫血模型中的红细胞生成。
DOI：
10.1016/j.jbc.2021.100988
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Sakamoto KM
中科院分区：
文献类型：
--
作者：
Wilkes MC;Jung K;Lee BE;Saxena M;Sathianathen RS;Mercado JD;Perez C;Flygare J;Narla A;Glader B;Sakamoto KM
Nemo-like kinase（NLK）是丝裂原活化蛋白激酶家族的成员，与其他丝裂原活化蛋白激酶家族成员共享高度保守的激酶结构域。NLK的激活有助于Diamond-Blackfan贫血（DBA）的发病机制，减少c-myb表达和雷帕霉素活性的机制靶点，因此是潜在的治疗靶点。与其他贫血不同，DBA的造血作用主要限于红系。核糖体基因突变诱导核糖体功能不全和蛋白质翻译减少，显著影响DBA患者骨髓中的早期红细胞生成。我们试图鉴定在核糖体功能不全中抑制NLK并增加红细胞生成的化合物。我们报告说，人参的活性成分，人参皂苷Rb 1，抑制NLK的表达，提高DBA的体外模型中的红细胞生成。人参皂苷Rb 1介导的NLK抑制通过上调miR-208发生，miR-208结合NLK mRNA的3′-UTR并靶向其降解。我们还比较了miR-208与二甲双胍介导的miR-26的上调。我们得出结论，通过独特的3′-UTR的miRNA结合靶向NLK表达是开发小分子抑制剂以靶向这种特定激酶的高度保守激酶结构域的挑战的可行替代方案。
Nemo-like kinase (NLK) is a member of the mitogen-activated protein kinase family of kinases and shares a highly conserved kinase domain with other mitogen-activated protein kinase family members. The activation of NLK contributes to the pathogenesis of Diamond–Blackfan anemia (DBA), reducing c-myb expression and mechanistic target of rapamycin activity, and is therefore a potential therapeutic target. Unlike other anemias, the hematopoietic effects of DBA are largely restricted to the erythroid lineage. Mutations in ribosomal genes induce ribosomal insufficiency and reduced protein translation, dramatically impacting early erythropoiesis in the bone marrow of patients with DBA. We sought to identify compounds that suppress NLK and increases erythropoiesis in ribosomal insufficiency. We report that the active component of ginseng, ginsenoside Rb1, suppresses NLK expression and improves erythropoiesis in in vitro models of DBA. Ginsenoside Rb1–mediated suppression of NLK occurs through the upregulation of miR-208, which binds to the 3′-UTR of NLK mRNA and targets it for degradation. We also compare ginsenoside Rb1–mediated upregulation of miR-208 with metformin-mediated upregulation of miR-26. We conclude that targeting NLK expression through miRNA binding of the unique 3′-UTR is a viable alternative to the challenges of developing small-molecule inhibitors to target the highly conserved kinase domain of this specific kinase.
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