Protein adduction causes non-mutational inhibition of p53 tumor suppressor.
Cell Rep
; 42(1): 112024, 2023 01 31.
Article
em En
| MEDLINE
| ID: mdl-36848235
ABSTRACT
p53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal adenocarcinoma, we find that p53 protein is adducted with reactive isolevuglandins (isoLGs), products of lipid peroxidation. Modification of p53 protein with isoLGs diminishes its acetylation and binding to the promoters of p53 target genes causing modulation of p53-dependent transcription. It also leads to accumulation of adducted p53 protein in intracellular amyloid-like aggregates that can be inhibited by isoLG scavenger 2-HOBA in vitro and in vivo. Taken together, our studies reveal a posttranslational modification of p53 protein that causes molecular aggregation of p53 protein and its non-mutational inactivation in conditions of DNA damage that may play an important role in human tumorigenesis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Proteína Supressora de Tumor p53
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos