Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression
Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression
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DOI：
10.1073/pnas.0911409107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Yang, Yingzi
中科院分区：
文献类型：
--
作者：
Song, Hai;Mak, Kinglun Kingston;Yang, Yingzi
通过细胞增殖和存活控制器官大小是一个基本的发育过程，其失调导致癌症。然而，在脊椎动物中，器官大小控制的分子机制仍然难以捉摸。在果蝇中，Hippo（Hpo）信号通路通过限制细胞生长和增殖以及促进细胞死亡来控制器官大小。在这里，我们调查了哺乳动物是否也需要Hpo途径来控制器官大小和成年组织的稳态。我们发现，Mst 1和Mst 2，果蝇Hpo的两个小鼠同源物，控制小鼠中一些但不是所有器官的大小，并且Mst 1和Mst 2通过限制细胞增殖和存活来充当肿瘤抑制剂。我们发现，Mst 1和Mst 2发挥多余的作用，并删除两者导致小鼠胚胎早期致死。重要的是，在出生后去除Mst 1和Mst 2后6个月，肿瘤在肝脏中发展，干/祖细胞大量增加。我们发现，Mst 1和Mst 2需要在体内控制雅普磷酸化和活性。有趣的是，在体内和体外，TNF α诱导的凋亡在Mst 1和Mst 2双突变细胞中被阻断。由于TNF α是一种通过调节细胞增殖和细胞死亡影响大多数器官的多效性炎性细胞因子，因此在不存在Mst 1和Mst 2的情况下，对TNF α诱导的细胞死亡的抗性也可能显著促进肿瘤形成。
Control of organ size by cell proliferation and survival is a fundamental developmental process, and its deregulation leads to cancer. However, the molecular mechanism underlying organ size control remains elusive in vertebrates. In Drosophila, the Hippo (Hpo) signaling pathway controls organ size by both restricting cell growth and proliferation and promoting cell death. Here we investigated whether mammals also require the Hpo pathway to control organ size and adult tissue homeostasis. We found that Mst1 and Mst2, the two mouse homologs of the Drosophila Hpo, control the sizes of some, but not all organs, in mice, and Mst1 and Mst2 act as tumor suppressors by restricting cell proliferation and survival. We show that Mst1 and Mst2 play redundant roles, and removal of both resulted in early lethality in mouse embryos. Importantly, tumors developed in the liver with a substantial increase of the stem/progenitor cells by 6 months after removing Mst1 and Mst2 postnatally. We show that Mst1 and Mst2 were required in vivo to control Yap phosphorylation and activity. Interestingly, apoptosis induced by TNF alpha was blocked in the Mst1 and Mst2 double-mutant cells both in vivo and in vitro. As TNF alpha is a pleiotropic inflammatory cytokine affecting most organs by regulating cell proliferation and cell death, resistance to TNF alpha-induced cell death may also contribute significantly to tumor formation in the absence of Mst1 and Mst2.