Nutrient-induced FNIP degradation by SCFß-TRCP regulates FLCN complex localization and promotes renal cancer progression.
Oncotarget
; 8(6): 9947-9960, 2017 Feb 07.
Article
em En
| MEDLINE
| ID: mdl-28039480
ABSTRACT
Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via ß-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFß-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Renais
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Proteínas de Transporte
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Estado Nutricional
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Proteínas Proto-Oncogênicas
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Proteínas Supressoras de Tumor
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Proteínas Ligases SKP Culina F-Box
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Proliferação de Células
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Síndrome de Birt-Hogg-Dubé
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Neoplasias Renais
Limite:
Animals
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Humans
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2017
Tipo de documento:
Article