About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation.
We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC).
Thus, this study offers a way to explain the chromosome instability in RCC and reveals a new direction for the tumor suppressor function of pVHL, which is independent of its E3 ubiquitin ligase activity.
Most cases of sporadic as well as familial ccRCC acquire somatic inactivating mutations of the von Hippel-Lindau tumor-suppressor gene, VHL. pVHL, VHL gene product and a protein member of the E3 ubiquitin ligase family, acts in normal cells to direct the degradation and clearance of the hypoxia inducible factor (HIF)alpha transcription factor family, such that in its absence, as in ccRCC, the HIF proteins stabilize, accumulate to supraphysiologic levels and activate the transcription of genes such as VEGF and PDGF, which contributes substantially to the physiology of the tumor, and has been assessed indirectly as a prognostic factor.
The VHL (von Hippel-Lindau) tumour-suppressor gene is inactivated in VHL disease and in sporadic cases of CCRCC [clear-cell RCC (renal cell carcinoma)]. pVHL (VHL protein) functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation.