Abstract
Advances in the understanding of the Hippo signaling as a key regulatory pathway of proliferation and apoptosis have provided mechanical insights for controlling organ size and tumorigenicity. Recently, much attention has been directed to the regulation of LATS1/2 (large tumor suppressor) kinases that phosphorylate YAP/TAZ, a transcriptional co-activator in the Hippo pathway, and control the level and nuclear localization of YAP/TAZ. In our recent work, we showed that deubiquitinase YOD1 stabilizes ITCH, and facilitates ITCH-mediated LATS1/2 ubiquitination and degradation, resulting in increased YAP/TAZ level. Furthermore, we found that the YOD1- ITCH-LATS1/2-YAP/TAZ signaling axis is controlled by the differential expression of miR-21 in a cell-density-dependent manner. Using a transgenic mouse model, we showed that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activitydependent manner. Moreover, a strong correlation was observed between YOD1 and YAP expression in liver cancer patients. Overall, our data suggest that YOD1 is a novel regulator of the Hippo pathway, and thereby a potential therapeutic target for liver cancer. [BMB Reports 2017; 50(6): 281-282].
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Apoptosis / genetics
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Apoptosis / physiology
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Cell Proliferation / genetics
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Cell Proliferation / physiology
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Endopeptidases / genetics
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Endopeptidases / metabolism*
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Hepatocytes / metabolism
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Hepatomegaly / enzymology*
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Hepatomegaly / metabolism*
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Humans
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Liver Neoplasms / enzymology*
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Liver Neoplasms / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology
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Thiolester Hydrolases / genetics
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Thiolester Hydrolases / metabolism*
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Transcription Factors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Phosphoproteins
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Repressor Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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YAP1 protein, human
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ITCH protein, human
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Ubiquitin-Protein Ligases
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LATS1 protein, human
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LATS2 protein, human
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Protein Serine-Threonine Kinases
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YOD1 protein, human
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Thiolester Hydrolases
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Endopeptidases