title: Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1.
abstract: The tumor suppressor gene RASSF1A is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologs of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic inasmuch as Hippo pathway components are rarely mutated in tumors. Here we show that Rassf1a homozygous knockout mice develop liver tumors. However, heterozygous deletion of Sav1 or codeletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A-binding partners by mass spectrometry identified the Hippo kinases MST1, MST2, and the oncogenic IκB kinase TBK1 as the most enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a(-/-) livers was more deregulated than that of Sav1(+/-) livers, and the transcriptome of Rassf1a(-/-), Sav1(+/-) livers was similar to that of Rassf1a(-/-) mice. We found that the levels of TBK1 protein were substantially upregulated in livers lacking Rassf1a. Furthermore, transcripts of several β-tubulin isoforms were increased in the Rassf1a-deficient livers presumably reflecting a role of RASSF1A as a microtubule-stabilizing protein. In human liver cancer, RASSF1A frequently undergoes methylation at the promoter but this was not observed for MST1, MST2, or SAV1. Our results suggest a multifactorial role of RASSF1A in suppression of liver carcinogenesis. Cancer Res; 76(9); 2824-35. ©2016 AACR.
authors.affiliation: Department of Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Cai
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Arthur X
authors.initials: AX
authors.lastname: Li
authors.affiliation: Department of Biology, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Limin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Walter
authors.initials: W
authors.lastname: Tsark
authors.affiliation: Institute for Genetics, Justus-Liebig-University, Giessen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dammann
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, California.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Vonderfecht
authors.affiliation: Department of Biology, Beckman Research Institute, City of Hope, Duarte, California. Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan. gerd.pfeifer@vai.org.
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
mesh_terms: D018248:Adenoma, Liver Cell / Q000235:genetics / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C496882:RASSF1 protein, mouse; C485935:Sav1 protein, mouse; D025521:Tumor Suppressor Proteins