論文 - 詳細
| RRC ID | 64988 |
|---|---|
| 著者 | Johmura Y, Sun J, Kitagawa K, Nakanishi K, Kuno T, Naiki-Ito A, Sawada Y, Miyamoto T, Okabe A, Aburatani H, Li S, Miyoshi I, Takahashi S, Kitagawa M, Nakanishi M. |
| タイトル | SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. |
| ジャーナル | Nat Commun |
| Abstract |
Recent evidence has revealed that senescence induction requires fine-tuned activation of p53, however, mechanisms underlying the regulation of p53 activity during senescence have not as yet been clearly established. We demonstrate here that SCF(Fbxo22)-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCF(Fbxo22) ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. Ectopic expression of a catalytic mutant of KDM4A stabilizes p53 and enhances p53 interaction with PHF20 in the presence of Fbxo22. SCF(Fbxo22)-KDM4A is required for the induction of p16 and senescence-associated secretory phenotypes during the late phase of senescence. Fbxo22(-/-) mice are almost half the size of Fbxo22(+/-) mice owing to the accumulation of p53. These results indicate that SCF(Fbxo22)-KDM4A is an E3 ubiquitin ligase that targets methylated p53 and regulates key senescent processes. |
| 巻・号 | 7 |
| ページ | 10574 |
| 公開日 | 2016-2-12 |
| DOI | 10.1038/ncomms10574 |
| PII | ncomms10574 |
| PMID | 26868148 |
| PMC | PMC4754341 |
| MeSH | Animals Cell Line, Tumor Cellular Senescence* Chromatin Immunoprecipitation F-Box Proteins / genetics* F-Box Proteins / metabolism* Flow Cytometry HEK293 Cells HeLa Cells Histone Demethylases / metabolism* Humans Immunoblotting Immunoprecipitation Jumonji Domain-Containing Histone Demethylases / metabolism* MCF-7 Cells Methylation Mice Mice, Knockout Oligonucleotide Array Sequence Analysis Real-Time Polymerase Chain Reaction Receptors, Cytoplasmic and Nuclear / genetics Receptors, Cytoplasmic and Nuclear / metabolism* Tumor Suppressor Protein p53 / metabolism* Ubiquitin-Protein Ligases / metabolism Ubiquitination |
| IF | 12.121 |
| リソース情報 | |
| ヒト・動物細胞 | MCF7(RCB1904) 293T(RCB2202) |