Hippo 信号通路调控 microprocessor，将细胞密度依赖的 miRNA 生物发生与癌症联系起来。
Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer.
机构信息
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
出版信息
Cell. 2014 Feb 27;156(5):893-906. doi: 10.1016/j.cell.2013.12.043.
Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here, we show that YAP, the downstream target of the tumor-suppressive Hippo-signaling pathway regulates miRNA biogenesis in a cell-density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA-processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding posttranscriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer.
在人类癌症中普遍观察到 microRNAs（miRNAs）的下调，并且其在肿瘤发生中可能具有因果作用。导致这种现象的机制仍知之甚少。在这里，我们表明 YAP（肿瘤抑制 Hippo 信号通路的下游靶标）以细胞密度依赖性方式调节 miRNA 的生物发生。在低密度时，核 YAP 结合并隔离 p72（DDX17），这是 miRNA 加工机制的调节成分。在高细胞密度下，Hippo 介导的 YAP 细胞质保留促进了 p72 与 Microprocessor 的结合，并与 pri-miRNAs 中的特定序列基序结合。Hippo 通路的失活或组成型激活的 YAP 的表达会导致细胞和肿瘤中广泛的 miRNA 抑制，并相应地诱导 MYC 表达的转录后诱导。因此，Hippo 通路将接触抑制调节与 miRNA 生物发生联系起来，并且可能是在癌症中观察到的广泛 miRNA 抑制的原因。
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