Jumonji 结构域包含蛋白 6（Jmjd6）是血管生成芽生所必需的，并且调节血管内皮生长因子受体 1 的剪接。
Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1.
机构信息
Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany.
出版信息
Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3276-81. doi: 10.1073/pnas.1008098108. Epub 2011 Feb 7.
Abstract
JmjC domain-containing proteins play a crucial role in the control of gene expression by acting as protein hydroxylases or demethylases, thereby controlling histone methylation or splicing. Here, we demonstrate that silencing of Jumonji domain-containing protein 6 (Jmjd6) impairs angiogenic functions of endothelial cells by changing the gene expression and modulating the splicing of the VEGF-receptor 1 (Flt1). Reduction of Jmjd6 expression altered splicing of Flt1 and increased the levels of the soluble form of Flt1, which binds to VEGF and placental growth factor (PlGF) and thereby inhibits angiogenesis. Saturating VEGF or PlGF or neutralizing antibodies directed against soluble Flt1 rescued the angiogenic defects induced by Jmjd6 silencing. Jmjd6 interacts with the splicing factors U2AF65 that binds to Flt1 mRNA. In conclusion, Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting.
摘要
JmjC 结构域蛋白通过作为蛋白羟化酶或去甲基化酶发挥作用，在控制基因表达方面发挥着关键作用，从而控制组蛋白甲基化或剪接。在这里，我们证明沉默 Jumonji 结构域蛋白 6（Jmjd6）通过改变基因表达和调节血管内皮生长因子受体 1（Flt1）的剪接来损害内皮细胞的血管生成功能。Jmjd6 表达的减少改变了 Flt1 的剪接，增加了可溶性 Flt1 的水平，可溶性 Flt1 与血管内皮生长因子（VEGF）和胎盘生长因子（PlGF）结合，从而抑制血管生成。用 VEGF 或 PlGF 或针对可溶性 Flt1 的中和抗体饱和可挽救 Jmjd6 沉默引起的血管生成缺陷。Jmjd6 与结合 Flt1 mRNA 的剪接因子 U2AF65 相互作用。总之，Jmjd6 调节 Flt1 的剪接，从而控制血管生成芽生。
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