| RRC ID |
70440
|
| 著者 |
Haraoka Y, Akieda Y, Nagai Y, Mogi C, Ishitani T.
|
| タイトル |
Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis.
|
| ジャーナル |
Nat Commun
|
| Abstract |
Most tumours are thought to arise through oncogenic cell generation followed by additional mutations. How a new oncogenic cell primes tumorigenesis by acquiring additional mutations remains unclear. We show that an additional TP53 mutation stimulates primary tumorigenesis by switching oncogene-induced senescence from a tumour suppressor to a driver. Zebrafish imaging reveals that a newly emerged oncogenic cell with the RasG12V mutation becomes senescent and is eliminated from the epithelia, which is prevented by adding a TP53 gain-of-function mutation (TP53R175H) into RasG12V cells. Surviving RasG12V-TP53R175H double-mutant cells senesce and secrete senescence-associated secretory phenotype (SASP)-related inflammatory molecules that convert neighbouring normal cells into SASP factor-secreting senescent cells, generating a heterogeneous tumour-like cell mass. We identify oncogenic cell behaviours that may control the initial human tumorigenesis step. Ras and TP53 mutations and cellular senescence are frequently detected in human tumours; similar switching may occur during the initial step of human tumorigenesis.
|
| 巻・号 |
13(1)
|
| ページ |
1417
|
| 公開日 |
2022-3-18
|
| DOI |
10.1038/s41467-022-29061-6
|
| PII |
10.1038/s41467-022-29061-6
|
| PMID |
35304872
|
| PMC |
PMC8933407
|
| MeSH |
Animals
Carcinogenesis / genetics
Cellular Senescence* / genetics
Mutation
Oncogenes / genetics
Tumor Suppressor Protein p53 / genetics*
Zebrafish* / genetics
|
| IF |
12.121
|
| リソース情報 |
| ゼブラフィッシュ |
Tg(krt4p:gal4; UAS:EGFP) |
