Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 4, Pages 1431-1436Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0911409107
Keywords
Hippo signaling; tumor suppressor; Yap phosphorylation
Categories
Funding
- National Human Genome Research Institute
- Welch Foundation [I-1603]
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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.
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