Journal Article

Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression

Yun, Kangsun, Hu, Jianxin, Garrett, Lisa, Jiang, Jin, Gao, Bin, Topol, Lilia, Chen, Yongbin, Wang, Cun-Yu, Song, Hai, Park, Ogyi, Simpson, R. Mark, Yang, Yingzi, Mak, Kinglun Kingston, Chang, Jia

2010

Overview

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 TNFα was blocked in the Mst1 and Mst2 double-mutant cells both in vivo and in vitro. As TNFα is a pleiotropic inflammatory cytokine affecting most organs by regulating cell proliferation and cell death, resistance to TNFα-induced cell death may also contribute significantly to tumor formation in the absence of Mst1 and Mst2.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adults / Animals / Apoptosis / Biological Sciences / Cell death / Cell growth / Cell Line / Cell lines / Cell Proliferation / Cell Survival / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Cells, Cultured / Cytokines / Deregulation / Drosophila / Gene Expression Regulation, Developmental / Hepatocyte Growth Factor - genetics / Hepatocyte Growth Factor - metabolism / Hepatocytes / homeostasis / Insects / Kinases / Liver / Liver - cytology / Liver - enzymology / Liver - growth & development / Liver Neoplasms - enzymology / Liver Neoplasms - genetics / Liver Neoplasms - pathology / Mammals / Mice / Mortality / Mutation / neoplasms / Organ Size / Phosphorylation / phosphotransferases (kinases) / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Rodents / Signal transduction / Stem cells / tumor necrosis factor-alpha / Tumor Necrosis Factor-alpha - metabolism / Tumors