| RRC ID |
83210
|
| Author |
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.
|
| Title |
Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex.
|
| Journal |
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.
|
| Volume |
42(1)
|
| Pages |
111972
|
| Published |
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
|
| Resource |
| Human and Animal Cells |
GSU(RCB2278)
TGBC11TKB(RCB1148) |
