PMID- 20080689
OWN - NLM
STAT- MEDLINE
DCOM- 20100312
LR  - 20230202
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 4
DP  - 2010 Jan 26
TI  - Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the 
      mammalian liver.
PG  - 1437-42
LID - 10.1073/pnas.0911427107 [doi]
AB  - How organ size is controlled in mammals is not currently understood. In 
      Drosophila the Hippo signaling pathway functions to suppress growth in imaginal 
      discs and has been suggested to control organ size. To investigate the role of 
      hippo signaling in regulation of mammalian organ size we have generated 
      conditional alleles of Sav1, mst1, and mst2, orthologs of Drosophila Salvador and 
      hippo, respectively. Specific deletion of both mst1 and mst2 in hepatocytes 
      results in significantly enlarged livers due to excessive proliferation. By the 
      age of 5-6 months, mst1/2 conditional mutant livers have multiple foci of liver 
      tumors, indicating that the combined activities of mst1 and mst2 act as redundant 
      tumor suppressors in hepatocytes. Similar findings were obtained with 
      liver-specific deletion of Sav1, a second core Hippo signaling component that 
      facilitates activation of mst1 and mst2. Tumors from sav1 mutants exhibited 
      varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. 
      Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional 
      mutants revealed a network of Hippo signaling regulated genes with specific 
      enrichment for genes involved in immune and inflammatory responses. Histological 
      and immunological characterization of mst1/2 double mutant liver tissues revealed 
      abundant accumulation of adult facultative stem cells termed oval cells in 
      periductal regions. Because oval cells induction is commonly associated with 
      liver injury and tumor formation, it is likely that these cells contribute to the 
      enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken 
      together, our results demonstrate that the Hippo signaling pathway is a critical 
      regulator of mammalian liver growth and a potent suppressor of liver tumor 
      formation.
FAU - Lu, Li
AU  - Lu L
AD  - Department of Biochemistry and Molecular Biology, University of Texas, M. D. 
      Anderson Cancer Center, Houston, TX 77030, USA.
FAU - Li, Ying
AU  - Li Y
FAU - Kim, Soo Mi
AU  - Kim SM
FAU - Bossuyt, Wouter
AU  - Bossuyt W
FAU - Liu, Pu
AU  - Liu P
FAU - Qiu, Qiong
AU  - Qiu Q
FAU - Wang, Yingdi
AU  - Wang Y
FAU - Halder, Georg
AU  - Halder G
FAU - Finegold, Milton J
AU  - Finegold MJ
FAU - Lee, Ju-Seog
AU  - Lee JS
FAU - Johnson, Randy L
AU  - Johnson RL
LA  - eng
GR  - R01 HD052785/HD/NICHD NIH HHS/United States
GR  - R01 HD060579/HD/NICHD NIH HHS/United States
GR  - HD052785/HD/NICHD NIH HHS/United States
GR  - HD060579/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100104
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Sav1 protein, mouse)
RN  - 0 (macrophage stimulating protein)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Serine-Threonine Kinase 3)
RN  - EC 2.7.11.1 (Stk3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins/genetics/*metabolism
MH  - Cell Transformation, Neoplastic/genetics/metabolism
MH  - Gene Expression Regulation, Developmental
MH  - Hepatocyte Growth Factor/genetics/*metabolism
MH  - Liver/growth & development/*metabolism
MH  - Liver Neoplasms/genetics/*metabolism/*pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Serine-Threonine Kinase 3
MH  - *Signal Transduction
MH  - Stem Cells/metabolism
MH  - Transcription, Genetic
PMC - PMC2824398
COIS- The authors declare no conflict of interest.
EDAT- 2010/01/19 06:00
MHDA- 2010/03/13 06:00
PMCR- 2010/01/04
CRDT- 2010/01/19 06:00
PHST- 2010/01/19 06:00 [entrez]
PHST- 2010/01/19 06:00 [pubmed]
PHST- 2010/03/13 06:00 [medline]
PHST- 2010/01/04 00:00 [pmc-release]
AID - 0911427107 [pii]
AID - 200911427 [pii]
AID - 10.1073/pnas.0911427107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42. doi: 
      10.1073/pnas.0911427107. Epub 2010 Jan 4.