VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma.
Animals
Caenorhabditis elegans
Carcinoma, Renal Cell
/ genetics
Cell Growth Processes
/ genetics
Cell Proliferation
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
HEK293 Cells
Humans
Kidney Neoplasms
/ genetics
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Regulatory-Associated Protein of mTOR
/ metabolism
Signal Transduction
/ genetics
Ubiquitination
/ genetics
Von Hippel-Lindau Tumor Suppressor Protein
/ physiology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 07 2021
21 07 2021
Historique:
received:
15
01
2021
accepted:
25
06
2021
entrez:
22
7
2021
pubmed:
23
7
2021
medline:
25
11
2021
Statut:
epublish
Résumé
Inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
Identifiants
pubmed: 34290272
doi: 10.1038/s41598-021-94132-5
pii: 10.1038/s41598-021-94132-5
pmc: PMC8295262
doi:
Substances chimiques
RPTOR protein, human
0
Regulatory-Associated Protein of mTOR
0
Von Hippel-Lindau Tumor Suppressor Protein
EC 2.3.2.27
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
VHL protein, human
EC 6.3.2.-
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
Pagination
14827Subventions
Organisme : NIH HHS
ID : P40 OD010440
Pays : United States
Informations de copyright
© 2021. The Author(s).
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