The role of the Von Hippel-Lindau tumor suppressor protein in clear cell renal carcinoma.
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Abstract Up to 88% of patients who suffer from clear cell renal carcinoma (ccRCC) have inactivating mutations in the Von Hippel-Lindau tumor suppressor gene. Also patients who have a certain type of the familial Von Hippel-Lindau syndrome, harboring a inactivating germline mutation in the VHL gene have a 60% chance of developing ccRCC. The VHL protein, pVHL, functions as an E3-ubiquitin ligase for Hypoxia Induced Factor α (HIFα) causing proteasomal mediated degradation of HIFα under normoxic conditions. In recent years other, non-HIFα related functions of pVHL, have been discovered. pVHL is also involved in cJun-NH2-kinase (JNK) regulation by acting as a scaffold for CK2, and regulation of the NFkB pathway by ubiquitinating atypical PKCs. pVHL also plays a role in the maintenance of the primary cilium. Biallelic loss of VHL causes aberrant transcription of HIFα target genes, increased proliferative potential through JNK signaling and nuclear accumulation of NFkB resulting in antiapoptotic factors. The loss of the primary cilium is thought to lead to the formation of renal cysts, which can result in ccRCC depending on other mutations accumulating in the cells. The complexity of ccRCC has made finding a suitable animal model for the disease very difficult. Several attempts have been made in mice so far but the most promising results to date have been attained in zebrafish.