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VHL Inactivation Induces HEF1 and Aurora Kinase A

Xu, JY; Li, HP; Wang, B; Xu, Y; Yang, JY; Zhang, XF; ... Esteban, MA; + view all (2010) VHL Inactivation Induces HEF1 and Aurora Kinase A. J AM SOC NEPHROL , 21 (12) 2041 - 2046. 10.1681/ASN.2010040345.

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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.

Type:Article
Title:VHL Inactivation Induces HEF1 and Aurora Kinase A
DOI:10.1681/ASN.2010040345
Keywords:TUMOR-SUPPRESSOR PROTEIN, RENAL-CELL CARCINOMA, PRIMARY CILIUM, INTRAFLAGELLAR TRANSPORT, E-CADHERIN, HYPOXIA, EXPRESSION, MIGRATION, DISEASE, HIF-1
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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