Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2
| Autor: | Carla V. Finkielstein, Tetsuya Gotoh, Xianlin Zou, Jingjing Liu, Anne M. Brown, Liang Jiang, Jae Kyoung Kim, Esther L. Wisdom |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system DNA Complementary Ubiquitin-Protein Ligases Period (gene) Circadian clock Biology Biochemistry 03 medical and health sciences Ubiquitin Neoplasms Humans Circadian rhythm Phosphorylation Molecular Biology Lysine Ubiquitination Proto-Oncogene Proteins c-mdm2 Period Circadian Proteins Cell Biology HCT116 Cells Circadian Rhythm Ubiquitin ligase Cell biology PER2 030104 developmental biology Ubiquitin ligase complex biology.protein Mdm2 Tumor Suppressor Protein p53 Protein Processing Post-Translational |
| Zdroj: | Science Signaling. 11 |
| ISSN: | 1937-9145 1945-0877 |
| Popis: | The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat-containing proteins (β-TrCPs), which are F-box-containing proteins that function as substrate recognition subunits of the SCFβ-TRCP ubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis. |
| Databáze: | OpenAIRE |
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