SCFFbl12 Increases p21Waf1/Cip1 Expression Level through Atypical Ubiquitin Chain Synthesis
| Autor: | Tadashi Baba, Ai Takebe, Tomoyuki Endo, Tomomi Fukuda, Yu Kigoshi, Fuminori Tsuruta, Hatsumi Miyahara, Jaehyun Kim, Kousuke Haratake, Yoshinori Kanemori, Tomoki Chiba, Manato Ebina |
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| Rok vydání: | 2016 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
0301 basic medicine Proteasome Endopeptidase Complex Plasma protein binding Autoantigens F-box protein 03 medical and health sciences 0302 clinical medicine Ubiquitin Cyclin-dependent kinase Neoplasms Humans Molecular Biology Regulation of gene expression biology Activator (genetics) F-Box Proteins Lysine Cyclin-dependent kinase 2 Ubiquitination Articles Cell Biology HCT116 Cells Molecular biology Up-Regulation Cell biology Gene Expression Regulation Neoplastic HEK293 Cells 030104 developmental biology Proteasome 030220 oncology & carcinogenesis biology.protein HeLa Cells Protein Binding |
| Zdroj: | Molecular and Cellular Biology. 36:2182-2194 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00174-16 |
| Popis: | The cyclin-dependent kinase (CDK) inhibitor p21 is an unstructured protein regulated by multiple turnover pathways. p21 abundance is tightly regulated, and its defect causes tumor development. However, the mechanisms that underlie the control of p21 level are not fully understood. Here, we report a novel mechanism by which a component of the SCF ubiquitin ligase, Fbl12, augments p21 via the formation of atypical ubiquitin chains. We found that Fbl12 binds and ubiquitinates p21. Unexpectedly, Fbl12 increases the expression level of p21 by enhancing the mixed-type ubiquitination, including not only K48- but also K63-linked ubiquitin chains, followed by promotion of binding between p21 and CDK2. We also found that proteasome activator PA28γ attenuates p21 ubiquitination by interacting with Fbl12. In addition, UV irradiation induces a dissociation of p21 from Fbl12 and decreases K63-linked ubiquitination, leading to p21 degradation. These data suggest that Fbl12 is a key factor that maintains adequate intracellular concentration of p21 under normal conditions. Our finding may provide a novel possibility that p21's fate is governed by diverse ubiquitin chains. |
| Databáze: | OpenAIRE |
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