GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Carcinoma, Transitional Cell
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
DNA Methylation
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Kelch-Like ECH-Associated Protein 1
/ genetics
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
NF-E2-Related Factor 2
/ genetics
Signal Transduction
/ genetics
Transplantation, Heterologous
Tumor Burden
/ genetics
Urinary Bladder Neoplasms
/ genetics
Journal
Science signaling
ISSN: 1937-9145
Titre abrégé: Sci Signal
Pays: United States
ID NLM: 101465400
Informations de publication
Date de publication:
18 08 2020
18 08 2020
Historique:
entrez:
21
8
2020
pubmed:
21
8
2020
medline:
3
11
2021
Statut:
epublish
Résumé
Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1 facilitated the nuclear accumulation of NRF2, led to constitutive activation of NRF2 signaling, and conferred resistance to the platinum drug cisplatin. Knockdown of GULP1 in UCB cells promoted tumor cell proliferation in vitro and enhanced tumor growth in vivo. In primary UCB, GULP1 silencing was more prevalent in muscle-invasive UCB compared to nonmuscle-invasive UCB. GULP1 knockdown cells showed resistance to cisplatin treatment. In parallel with decreased
Identifiants
pubmed: 32817372
pii: 13/645/eaba0443
doi: 10.1126/scisignal.aba0443
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
GULP1 protein, human
0
KEAP1 protein, human
0
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P50 CA098252
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163594
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.