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James Gnarra, PhD

VHL and renal cancer

The von Hippel-Lindau (VHL) tumor suppressor is inactivated in patients with von Hippel-Lindau disease, an inherited cancer syndrome, and in most sporadic clear cell renal carcinomas (ccRCC).  VHL-inactivated tumors over-express hypoxia-responsive gene products, including the pro-angiogenic vascular endothelial growth factor (VEGF).  Re-expression of wild type VHL in ccRCC cell lines results in down-regulation of expression of these gene products.  A long-term goal of our work is to understand the mechanisms through which VHL controls expression of hypoxia-responsive angiogenic growth factors and how VHL inactivation leads to tumorigenesis.

The VHL protein is in an E3 ubiquitin ligase in a Cullin-RING ligase (CRL) complex.  VHL controls protein levels of the hypoxia-inducible transcription factor (HIF) alpha subunits.  Under normal oxygen conditions, VHL binds to prolyl-hydroxylated HIF alpha subunits and targets them for ubiquitylation and proteasomal degradation.  Under hypoxic conditions, pVHL levels are reduced and HIF alpha subunits are stabilized, resulting in induction of a robust HIF-mediated transcription response.  The absence of functional VHL in ccRCC results in constitutively elevated HIF alpha levels even in the presence of normal environmental oxygen levels.

Our ongoing studies focus on VHL activity and the effects of VHL inactivation in two areas.  We are working to understand (1) mechanisms of regulation of hypoxia-responsive gene products, such as VEGF, at the transcriptional and post-transcriptional levels, and (2) the role for VHL in cell cycle regulation, and in particular mitotic checkpoint controls.

Recent Publications

1. Liu, W., Xin, H., Eckert, D.T., Brown, J.A., and Gnarra, J.R.  Hypoxia and cell cycle regulation of the von Hippel-Lindau tumor suppressor.  Oncogene, 30, 21–31, 2011. 

2. Nielsen,S.M., Rubinstein, W.S., Thull, D.L., Armstrong, M.J., Feingold, E., Stang, M.T., Gnarra, J.R., and Carty, S.E. Genotype-phenotype correlations of pheochromocytoma in two large von Hippel-Lindau (VHL) type 2A kindreds with different missense mutations.  American Journal of Medical Genetics, 155, 168-173, 2011. 

Contact Information

Department of Urology
Shadyside Medical Center
5200 Centre Ave., Suite G37
Pittsburgh, PA 15232
Telephone: 412-623-3914
Fax: 412-623-3907

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