文章基本信息

标题：Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression
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作者：Hai Song ; Kinglun Kingston Mak ; Lilia Topol 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：4
页码：1431-1436
DOI：10.1073/pnas.0911409107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：Hippo signaling ; tumor suppressor ; Yap phosphorylation