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Analysis of liver tumor-prone mouse models of the Hippo kinase scaffold proteins Rassf1a and Sav1

Zhang, Xiaoying and Guo, Cai and Wu, Xiwei and Li, Arthur X. and Liu, Limin and Tsark, Walter and Dammann, Reinhard and Shen, Hui and Vonderfecht, Steven L. and Pfeifer, Gerd P. (2016) Analysis of liver tumor-prone mouse models of the Hippo kinase scaffold proteins Rassf1a and Sav1. Cancer Research, 76 (9). pp. 2824-2835. ISSN 0008-5472. PMCID PMC4873365. doi:10.1158/0008-5472.CAN-15-3010.

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The tumor suppressor gene RASSF1A is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologues 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 co-deletion 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 IkB 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 beta 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.

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Additional Information:© 2016 American Association for Cancer Research. Received November 3, 2015. Revision received January 28, 2016. Accepted February 25, 2016. This work was supported by a grant of the University of California Tobacco-Related Disease Research Program (17RT-0116) and by NIH grant CA084469 to GPP.
Funding AgencyGrant Number
Tobacco-Related Disease Research Program (TRDRP)17RT-0116
Issue or Number:9
PubMed Central ID:PMC4873365
Record Number:CaltechAUTHORS:20160321-082116169
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Official Citation:Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1 Xiaoying Zhang, Cai Guo, Xiwei Wu, Arthur X. Li, Limin Liu, Walter Tsark, Reinhard Dammann, Hui Shen, Steven L. Vonderfecht, and Gerd P. Pfeifer Cancer Res May 1, 2016 76:2824-2835; Published OnlineFirst March 15, 2016; doi:10.1158/0008-5472.CAN-15-3010
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65506
Deposited By: Ruth Sustaita
Deposited On:30 Mar 2016 19:59
Last Modified:10 Nov 2021 23:46

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