|Title:||Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis||Authors:||Xu D.
|Issue Date:||2015||Publisher:||Nature Publishing Group||Journal Volume:||6||Source:||Nature Communications||Abstract:||
Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy. ? 2015 Macmillan Publishers Limited. All rights reserved.
|ISSN:||20411723||DOI:||10.1038/ncomms7641||SDG/Keyword:||cyclin dependent kinase 8; histone; protein macroH2A1; protein p27; S phase kinase associated protein 2; unclassified drug; CDK8 protein, human; Cdk8 protein, mouse; cyclin dependent kinase 8; cyclin dependent kinase inhibitor 1B; histone; macroH2A histone; S phase kinase associated protein; ubiquitin protein ligase; cancer; disease treatment; gene expression; ploidy; protein; rodent; tumor; womens health; animal cell; animal experiment; animal model; Article; breast cancer; breast carcinogenesis; cancer growth; cancer patient; complex formation; controlled study; female; G2 phase cell cycle checkpoint; gene expression; human; human cell; M phase cell cycle checkpoint; mouse; nonhuman; protein degradation; protein expression; tumor model; ubiquitination; animal; breast tumor; carcinogenesis; carcinoma; fibroblast; G2 phase cell cycle checkpoint; genetics; knockout mouse; metabolism; tumor cell line; Animals; Breast Neoplasms; Carcinogenesis; Carcinoma; Cell Line, Tumor; Cyclin-Dependent Kinase 8; Cyclin-Dependent Kinase Inhibitor p27; Fibroblasts; G2 Phase Cell Cycle Checkpoints; Histones; Humans; Mice; Mice, Knockout; S-Phase Kinase-Associated Proteins; SKP Cullin F-Box Protein Ligases; Ubiquitination
|Appears in Collections:||生物化學暨分子生物學科研究所|
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