期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：24
页码：11122-11127
DOI：10.1073/pnas.1005262107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Here we demonstrate that reprogramming steroid receptor coactivator-3 (SRC-3) function by changing its posttranslational modification (PTM) code drastically influences systems biology. These findings support the physiological importance of PTMs in directing in vivo functions of a master coregulator. We previously reported that the transactivation potential of SRC-3 is controlled in part by PTMs, although this data emanated from in vitro studies. To test the physiological implications of PTMs on SRC-3, we developed a knock-in mouse model containing mutations at four conserved phosphorylation sites. These mice displayed a systems biology phenotype with increased body weight and adiposity, coupled with reduced peripheral insulin sensitivity. Collectively, these phenotypes result from increased IGF1 signaling, due to elevated IGFBP3 levels. We provide convincing evidence that these mutations in SRC-3 promoted enhanced transcription of the IGFBP3 gene and globally influenced growth and metabolism. Consequently, these mice displayed increased liver tumorigenesis, which likely results from elevated IGF1 signaling.
