論文 - 詳細
| RRC ID | 83210 |
|---|---|
| 著者 | Wang X, Xie Q, Ji Y, Yang J, Shen J, Peng F, Zhang Y, Jiang F, Kong X, Ma W, Liu D, Zheng L, Qing C, Lang JY. |
| タイトル | Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex. |
| ジャーナル | Cell Rep |
| Abstract |
KRAS is widely mutated in human cancers, resulting in unchecked tumor proliferation and metastasis, which makes identifying KRAS-targeting therapies a priority. Herein, we observe that mutant KRAS specifically promotes the formation of the ERK2-p53 complex in stomach/colorectal tumor cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through a hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumors. Our study shows an important role for the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer. |
| 巻・号 | 42(1) |
| ページ | 111972 |
| 公開日 | 2023-1-31 |
| DOI | 10.1016/j.celrep.2022.111972 |
| PII | S2211-1247(22)01876-9 |
| PMID | 36641751 |
| MeSH | Colorectal Neoplasms* / genetics Colorectal Neoplasms* / metabolism Humans Phosphorylation Proto-Oncogene Proteins p21(ras)* / genetics Proto-Oncogene Proteins p21(ras)* / metabolism Stomach Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism |
| IF | 8.109 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | GSU(RCB2278) TGBC11TKB(RCB1148) |