Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
| Autor: | Jinjia Zhang, Dawang Zhou, Zhenyu Yin, Qinghua Chen, Hongtan Wu, Jing Geng, Lanfen Chen, Luyao Wei, Changnan Jin, Fan Fuqin, Hong Rui Wang, Shihao Zhang, Bin Zhao, Kwang Huei Lin, Xianming Deng, Mingting Jiang, Jau-Song Yu, Qingxu Liu, Funiu Qin, Lixin Hong, Suyuan Ji, Xiufeng Sun, Randy L. Johnson, Xin Fan, Jing Tian |
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| Rok vydání: | 2015 |
| Předmět: |
MST1
Transcription Genetic Carcinogenesis Regulator General Physics and Astronomy Cell Cycle Proteins Endoplasmic Reticulum Serine-Threonine Kinase 3 environment and public health chemistry.chemical_compound Tissue homeostasis Mice Knockout Multidisciplinary Hepatocyte Growth Factor Effector Liver Neoplasms Hep G2 Cells Organ Size Cell biology Liver Poly(ADP-ribose) Polymerases Signal Transduction endocrine system Blotting Western Molecular Sequence Data Protein Serine-Threonine Kinases Biology Models Biological digestive system General Biochemistry Genetics and Molecular Biology Taurochenodeoxycholic Acid Proto-Oncogene Proteins Animals Humans Adaptor Proteins Signal Transducing Hippo signaling pathway Endoplasmic reticulum fungi YAP-Signaling Proteins Tauroursodeoxycholic acid General Chemistry Phosphoproteins Activating Transcription Factor 6 Mice Inbred C57BL chemistry Mutation biological sciences Hepatocytes Unfolded Protein Response Unfolded protein response |
| Zdroj: | Nature Communications. 6 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms7239 |
| Popis: | The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. Here we find that loss of Mst1/2, the mammalian Hippo orthologues, or their regulator WW45, leads to a remarkably enlarged endoplasmic reticulum (ER) size-associated UPR. Intriguingly, attenuation of the UPR by tauroursodeoxycholic acid (TUDCA) diminishes Mst1/2 mutant-driven liver overgrowth and tumorigenesis by promoting nuclear exit and degradation of Hippo downstream effector Yap. Yap is required for UPR activity and ER expansion to alleviate ER stress. During the adaptive stage of the UPR, PERK kinase-eIF2α axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Significantly, the deregulation of UPR signals associated with Yap activation is found in a substantial fraction of human hepatocellular carcinoma (HCC). Thus, we conclude Yap integrates Hippo and UPR signalling to control liver size and tumorigenesis. |
| Databáze: | OpenAIRE |
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