Protein adduction causes non-mutational inhibition of p53 tumor suppressor.
CP: Cancer
Helicobacter pylori
esophageal cancer
p53
p73
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
31 01 2023
31 01 2023
Historique:
received:
05
04
2022
revised:
04
06
2022
accepted:
09
01
2023
entrez:
27
2
2023
pubmed:
28
2
2023
medline:
3
3
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36848235
pii: S2211-1247(23)00035-9
doi: 10.1016/j.celrep.2023.112024
pmc: PMC9989503
mid: NIHMS1870549
pii:
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Amyloidogenic Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
112024Subventions
Organisme : NCI NIH HHS
ID : R01 CA138833
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206564
Pays : United States
Organisme : BLRD VA
ID : IK6 BX006300
Pays : United States
Organisme : BLRD VA
ID : I01 BX002115
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA268991
Pays : United States
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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