HIF-2alpha downregulation in the absence of functional VHL is not sufficient for renal cell differentiation.
Hughes MD, Kapllani E, Alexander AE, Burk RD, Schoenfeld AR.
Department of Biology, Adelphi University, Garden City, NY 11530-0701, USA. hughes@adelphi.edu
BACKGROUND: Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary as well as sporadic clear cell renal carcinomas. The product of the VHL gene, pVHL, acts to target hypoxia-inducible factor alpha (HIF-alpha) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2alpha in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2alpha toward cellular pVHL activities. RESULTS: Knockdown of HIF-2alpha resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2alpha regulation. However, cellular morphological changes and downregulation of integrins alpha5 and beta1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2alpha reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2alpha knockdown cells, indicating that these pVHL functions may occur independently of HIF-2alpha downregulation. CONCLUSION: These results indicate that HIF-2alpha regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2alpha dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis.
PMID: 17598890 [PubMed]PMCID: PMC1919349