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Transcriptional and translational regulation of C/EBPbeta-HDAC1 protein complexes controls different levels of p53, SIRT1, and PGC1alpha proteins at the early and late stages of liver cancer

moviecapture 添加于 2013-12-22 23:45 | 1515 次阅读 | 0 个评论

作者
Jin J, Iakova P, Jiang Y, Lewis K, Sullivan E, Jawanmardi N, Donehower L, Timchenko L, Timchenko NA
摘要
Cancer changes biological processes in the liver by altering gene expression at the levels of transcription, translation, and protein modification. The RNA binding protein CUGBP1 is a key regulator of translation of CCAAT enhancer binding protein beta and histone deacetylase 1 (HDAC1). These proteins form complexes that are involved in the regulation of liver biology. Here we show a critical role of the translational activation of CCAAT/enhancer binding protein beta-HDAC1 complexes in the development of liver cancer mediated by diethylnitrosamine. We found that diethylnitrosamine increases the levels of CUGBP1 and activates CUGBP1 by phosphorylation, leading to the formation of the CUGBP1-eIF2 complex, which is an activator of translation of CUGBP1-dependent mRNAs. The elevation of the CUGBP1-eIF2 complex increases translation of C/EBPbeta and HDAC1, resulting in an increase of C/EBPbeta-HDAC1 complexes at later stages of liver cancer. We found that C/EBPbeta-HDAC1 complexes repress promoters of three key regulators of liver functions: p53, SIRT1, and PGC1alpha. As the result of this suppression, the p53-, SIRT1-, and PGC1alpha-dependent downstream pathways are reduced, leading to increased liver proliferation. We also found that the proper regulation of C/EBPbeta-HDAC1 complexes is required for the maintenance of biological levels of p53, SIRT1, and PGC1alpha in quiescent livers and at early stages of liver cancer. Taken together, these studies showed that the development of liver cancer includes a tight regulation of levels of C/EBPbeta-HDAC1 complexes on the levels of transcription, translation, and posttranslational modifications.
详细资料
- 关键词: Animals; Base Sequence; CCAAT-Enhancer-Binding Protein-beta/*metabolism; Cell Proliferation; Diethylnitrosamine/pharmacology; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heat-Shock Proteins/metabolism; Histone Deacetylase 1/*metabolism; Humans; Liver Neoplasms/chemically induced/*metabolism; Mice; Models, Biological; Molecular Sequence Data; Sirtuin 1/*metabolism; Trans-Activators/*metabolism; Transcription Factors/metabolism; Transcriptional Activatio ...
- 文献种类:期刊
- 期刊名称: The Journal of Biological Chemistry
- 期刊缩写: J Biol Chem
- 期卷页: 2013年第288卷第20期 14451-14462页
- 地址: Huffington Center on Aging and Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
- ISBN: 0021-9258
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