Regulatory mechanism of the tumor suppressive Hippo pathway

抑癌Hippo通路的调控机制

• 批准号: 22590267
• 负责人: HATA Yutaka
• 金额: $ 2.91万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590267/
• 关键词: 癌; シグナル伝達; キナーゼ; tumor suppressor; 小分子化合物

To clarify the molecular mechanism that regulates the mammalian Hippo pathway, we first searched for molecules that functionally and physically interact with the known components such as FAT4, Merlin, RASSFs, Salvador, and MOB1. However, this attempt was not successful. We subsequently established several cell-based assay systems to monitor the activity of the Hippo pathway and searched for chemical compounds that up-regulate or down-regulate the Hippo pathway. We found that ss-adrenergic stimulants up-regulate the Hippo pathway. This is the first study to report the implication of G protein-coupled receptors in the regulation of the Hippo pathway. We have additionally obtained several candidate compounds that modulate the Hippo pathway. These compounds include candidates that promote myogenesis and that inhibit cancer invasiveness and metastasis. We are currently analyzing how these compounds exhibit the effects and trying to find out new regulatory mechanisms of the Hippo pathway as well as to develop useful reagents for the treatment of muscle atrophy and cancer. We also analyzed Caenorhabditis elegans homologs of RASSF and YAP, both of which are the components of the Hippo pathway, and found that the Hippo pathway is not conserved in Caenorhabditis elegans. However the findings about Caenorhabditis elegans RASSF homolog has shed light on the putative function of RASSF, which may be useful for the future study in the mammalian Hippo pathway.

为了阐明调节哺乳动物Hippo通路的分子机制，我们首先寻找与已知组分如FAT 4、Merlin、RASSFs、萨尔瓦多和MOB 1在功能和物理上相互作用的分子。然而，这一尝试并没有成功。我们随后建立了几个基于细胞的测定系统来监测Hippo通路的活性，并寻找上调或下调Hippo通路的化合物。我们发现β-肾上腺素能兴奋剂上调Hippo通路。这是第一个研究报告的影响G蛋白偶联受体的调节海马途径。我们还获得了几种调节Hippo途径的候选化合物。这些化合物包括促进肌生成和抑制癌症侵袭和转移的候选物。我们目前正在分析这些化合物如何发挥作用，并试图找出Hippo通路的新调控机制，以及开发用于治疗肌肉萎缩和癌症的有用试剂。我们还分析了秀丽隐杆线虫的RASSF和雅普同源物，这两者都是Hippo途径的组分，并发现Hippo途径在秀丽隐杆线虫中不保守。然而，秀丽隐杆线虫RASSF同源物的发现为RASSF的功能研究提供了新的思路，为进一步研究哺乳动物Hippo信号通路奠定了基础。

项目成果

SynArfGEF is a guanine nucleotide exchange factor for Arf6 and localizes preferentially at post-synaptic specializations of inhibitory synapse

SynArfGEF 是 Arf6 的鸟嘌呤核苷酸交换因子，优先定位于抑制性突触的突触后特化

• 发表时间: 2011
• 期刊: J. Neurochem
• 作者: Fukaya M;Kamata A;Hara Y;Tamaki H;Katsumata O;Ito N;Takeda S;Hata Y;Suzuki T;Watanabe M;Harvey RJ,Sakagami H
• 通讯作者: Harvey RJ,Sakagami H

Preparation of tumor-initiating cells using the mutants of TAZ and YAP

使用TAZ和YAP突变体制备肿瘤起始细胞

• 发表时间: 2010
• 作者: Kobayashi A;Tsukide T;Miyasaka T;Morita T;Mizoroki T;Saito Y;Ihara Y;Takashima A;Noguchi N;Fukamizu A;Hirotsu Y;Ohtsuji M;Katsuoka F;Yamamoto M;Takehiko Ueyama;Takehiko Ueyama;Hata Y.;Hata Y
• 通讯作者: Hata Y

Expression of RASSF6 in kidney and the implication of RASSF6 and the Hippo pathway in the sorbitol-induced apoptosis in renal proximal tubular epithelial cells.

• DOI: 10.1093/jb/mvs056
• 发表时间: 2012-07
• 期刊: Journal of biochemistry
• 影响因子: 2.7
• 作者: Kanchanamala Withanage;K. Nakagawa;Mitsunobu Ikeda;H. Kurihara;Takumi Kudo;Zeyu Yang;A. Sakane;Takuya Sasaki;Y. Hata

The RASSF3 candidate tumor suppressor induces apoptosis and G1/S arrest via p53

RASSF3 候选肿瘤抑制因子通过 p53 诱导细胞凋亡和 G1/S 停滞

• 发表时间: 2012
• 期刊: Cancer Res
• 影响因子: 11.2
• 作者: Kudo T;et al
• 通讯作者: et al

足場タンパクin「トランスポートソーム-膜輸送研究の源流から未来へ向けて」In press

“运输体 - 从膜运输研究的起源到未来”中的支架蛋白

• 发表时间: 2011
• 作者: 畑裕;池田光伸
• 通讯作者: 池田光伸