Primary research

HIF-2α downregulation in the absence of functional VHL is not sufficient for renal cell differentiation

Michael D Hughes^{* 1} , Erilda Kapllani^{* 1} , Ashlynn E Alexander¹ , Robert D Burk² and Alan R Schoenfeld¹

¹Department of Biology, Adelphi University, Garden City, NY 11530-0701, USA

²Departments of Microbiology and Immunology, Pediatrics, and Epidemiology and Social Medicine, Marion Bessin Liver Research Center and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA

author email corresponding author email* Contributed equally

Cancer Cell International 2007, 7:13doi:10.1186/1475-2867-7-13

Published:	28 June 2007

Abstract

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-α) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2α in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2α toward cellular pVHL activities.

Results

Knockdown of HIF-2α resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2α regulation. However, cellular morphological changes and downregulation of integrins α5 and β1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2α reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2α knockdown cells, indicating that these pVHL functions may occur independently of HIF-2α downregulation.

Conclusion

These results indicate that HIF-2α regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2α dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis.