1. SUMOylation of HNF4α regulates protein stability and hepatocyte function
- Author
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Stuart J. Forbes, David C. Hay, Ellis Jaffray, Zara Hannoun, Claire N. Medine, James R. Black, Liang Zhu, Sebastian Greenhough, James A. Ross, Wenli Zhou, Ronald T. Hay, John P. Iredale, and Ian Wilmut more...
- Subjects
HNF4 alpha ,Cellular differentiation ,Hepatocyte function ,SUMO protein ,Cell-based modelling ,Transthyretin ,ACTIVATION ,0302 clinical medicine ,Protein stability ,DOMAIN ,Catalytic Domain ,BINDING ,Hepatocyte ,Nuclear protein ,Tissue homeostasis ,Hepatocyte differentiation ,0303 health sciences ,Protein Stability ,030302 biochemistry & molecular biology ,Nuclear Proteins ,Cell Differentiation ,Cell biology ,DIFFERENTIATION ,Liver ,Hepatocyte Nuclear Factor 4 ,Biochemistry ,030220 oncology & carcinogenesis ,Small Ubiquitin-Related Modifier Proteins ,Research Article ,Signal Transduction ,Protein sumoylation ,RNF4 ,Biology ,UBIQUITIN LIGASE ,03 medical and health sciences ,Humans ,HNF4α ,Transcription factor ,Embryonic Stem Cells ,030304 developmental biology ,HUMAN BLASTOCYSTS ,Ubiquitin ,Ubiquitination ,Sumoylation ,STEM-CELL LINES ,Cell Biology ,p450 ,Oxidative Stress ,Hepatocyte nuclear factor 4 ,SUMO ,hESCs ,Hepatocytes ,Transcription Factors - Abstract
Summary The coordination of signalling pathways within the cell is vital for normal human development and post-natal tissue homeostasis. Gene expression and function is therefore tightly controlled at a number of levels. We investigated the role that post-translational modifications play during human hepatocyte differentiation. In particular, we examined the role of the small ubiquitin-like modifier (SUMO) proteins in this process. We used a human embryonic stem cell (hESC)-based model of hepatocyte differentiation to follow changes in protein SUMOylation. Moreover, to confirm the results derived from our cell-based system, we performed in vitro conjugation assays to characterise SUMO modification of a key liver-enriched transcription factor, HNF4α. Our analyses indicate that SUMOylation plays an important role during hepatocellular differentiation and this is mediated, in part, through regulation of the stability of HNF4α in a ubiquitin-dependent manner. Our study provides a better understanding of SUMOylation during human hepatocyte differentiation and maturation. Moreover, we believe the results will stimulate interest in the differentiation and phenotypic regulation of other somatic cell types. more...
- Published
- 2012
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