Department of Biochemistry, School of Medicine, Chungbuk National University, Cheongju, South Korea.
J Cell Physiol. 2012 Feb;227(2):839-49. doi: 10.1002/jcp.22887.
Recent genetic screens of fly mutants and molecular analysis have revealed that the Hippo (Hpo) pathway controls both cell proliferation and cell death. Deregulation of its human counterpart (the MST pathway) has been implicated in human cancers. However, how this pathway is linked with the known tumor suppressor network remains to be established. RUNX3 functions as a tumor suppressor of gastric cancer, lung cancer, bladder cancer, and colon cancer. Here, we show that RUNX3 is a principal and evolutionarily conserved component of the MST pathway. SAV1/WW45 facilitates the close association between MST2 and RUNX3. MST2, in turn, stimulates the SAV1-RUNX3 interaction. In addition, we show that siRNA-mediated RUNX3 knockdown abolishes MST/Hpo-mediated cell death. By establishing that RUNX3 is an endpoint effector of the MST pathway and that RUNX3 is capable of inducing cell death in cooperation with MST and SAV1, we define an evolutionarily conserved novel regulatory mechanism loop for tumor suppression in human cancers.
最近的果蝇突变体基因筛选和分子分析表明，Hippo（Hpo）通路既控制细胞增殖又控制细胞死亡。其人类对应物（MST 通路）的失调与人类癌症有关。然而，该途径如何与已知的肿瘤抑制器网络联系在一起还有待确定。RUNX3 是胃癌、肺癌、膀胱癌和结肠癌的肿瘤抑制因子。在这里，我们表明 RUNX3 是 MST 通路的主要和进化上保守的组成部分。SAV1/WW45 促进 MST2 和 RUNX3 之间的紧密关联。反过来，MST2 刺激 SAV1-RUNX3 相互作用。此外，我们表明，siRNA 介导的 RUNX3 敲低可消除 MST/Hpo 介导的细胞死亡。通过确定 RUNX3 是 MST 通路的终点效应因子，并且 RUNX3 能够与 MST 和 SAV1 合作诱导细胞死亡，我们定义了一个在人类癌症中具有进化保守的新型肿瘤抑制调节机制循环。
