VHL inactivation induces HEF1 and Aurora kinase A.
J Am Soc Nephrol
; 21(12): 2041-6, 2010 Dec.
Article
em En
| MEDLINE
| ID: mdl-20864688
ABSTRACT
The ciliary hypothesis for cystic renal diseases postulates that most of these conditions result from abnormalities in the primary cilium, a microtubule-based structure that acts as a sensor for extracellular cues. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to renal cysts and clear cell renal cell carcinoma. VHL plays a critical role in the formation of primary cilia in kidney epithelium, but the underlying mechanisms are poorly understood. Here, we demonstrate that VHL inactivation induces HEF1/Cas-L/NEDD9 and Aurora kinase A via the stabilization of hypoxia-inducible factors 1 and 2. Aurora kinase A is a mitotic kinase commonly upregulated in cancer that causes regression of the primary cilium by promoting histone deacetylase-dependent tubulin depolymerization of the ciliary axoneme. HEF1/Cas-L/NEDD9 is a component of focal adhesions that has a prominent role in inducing metastasis and that colocalizes with Aurora kinase A at the centrosome, thereby enhancing the harmful effect of Aurora kinase A on the cilium. Suppression of this pathway improved the formation of primary cilia and reduced cell motility in VHL-defective renal cancer cells. Our results highlight the gatekeeper role of VHL in the kidney epithelium.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
/
Carcinoma de Células Renais
/
Proteínas Serina-Treonina Quinases
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Proteínas Adaptadoras de Transdução de Sinal
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Doenças Renais Císticas
/
Proteína Supressora de Tumor Von Hippel-Lindau
/
Neoplasias Renais
Tipo de estudo:
Diagnostic_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Am Soc Nephrol
Assunto da revista:
NEFROLOGIA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
China