This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaelin, W. G. Search for Related Content PubMed PubMed Citation Articles by Kaelin, W. G., Jr.

The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer

Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts

The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in >50% of sporadic clear cell renal cell carcinomas. Germ-line VHL mutations give rise to VHL disease, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas) and renal cell carcinomas. In this setting, VHL inactivation gives rise to premalignant renal cysts. Additional genetic alterations are presumably required for conversion of these cysts to renal cell carcinomas. Restoration of VHL function in VHL–/– renal cell carcinomas is sufficient to inhibit tumorigenesis in vivo. On the basis of these and other data, VHL appears to be a critical gatekeeper with respect to the development of renal cell carcinoma. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL, accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor . We have demonstrated that inhibition of HIF is necessary and sufficient for tumor suppression by pVHL in renal cell carcinoma nude mouse xenograft assays. This provides a rationale for treating VHL–/– renal cell carcinoma with inhibitors of HIF or its downstream targets. Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth.

This article has been cited by other articles:

				M. D. Michaelson, O. Iliopoulos, D. F. McDermott, F. J. McGovern, M. G. Harisinghani, and E. Oliva Case 17-2008 -- A 63-Year-Old Man with Metastatic Renal-Cell Carcinoma N. Engl. J. Med., May 29, 2008; 358(22): 2389 - 2396. [Full Text] [PDF]

				W. K. Rathmell, W. M. Stadler, and B. I. Rini Rational Therapeutic Choices and Strategies for Patients with Metastatic Renal Cancer ASCO Educational Book, January 1, 2008; 2008(1): 192 - 198. [Abstract] [Full Text] [PDF]

				C. W. Ryan, B. H. Goldman, P. N. Lara Jr, P. C. Mack, T. M. Beer, C. M. Tangen, D. Lemmon, C.-X. Pan, H. A. Drabkin, and E. D. Crawford Sorafenib With Interferon Alfa-2b As First-Line Treatment of Advanced Renal Carcinoma: A Phase II Study of the Southwest Oncology Group J. Clin. Oncol., August 1, 2007; 25(22): 3296 - 3301. [Abstract] [Full Text] [PDF]

				L. Li, L. Zhang, X. Zhang, Q. Yan, Y. A. Minamishima, A. F. Olumi, M. Mao, S. Bartz, and W. G. Kaelin Jr. Hypoxia-Inducible Factor Linked to Differential Kidney Cancer Risk Seen with Type 2A and Type 2B VHL Mutations Mol. Cell. Biol., August 1, 2007; 27(15): 5381 - 5392. [Abstract] [Full Text] [PDF]

				J. Brugarolas Renal-Cell Carcinoma -- Molecular Pathways and Therapies N. Engl. J. Med., January 11, 2007; 356(2): 185 - 187. [Full Text] [PDF]

				R. J. Motzer and R. M. Bukowski Targeted Therapy for Metastatic Renal Cell Carcinoma J. Clin. Oncol., December 10, 2006; 24(35): 5601 - 5608. [Abstract] [Full Text] [PDF]

				B. Schermer, C. Ghenoiu, M. Bartram, R. U. Muller, F. Kotsis, M. Hohne, W. Kuhn, M. Rapka, R. Nitschke, H. Zentgraf, et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth J. Cell Biol., November 20, 2006; 175(4): 547 - 554. [Abstract] [Full Text] [PDF]

				O. Iliopoulos, G. Chan-Smutko, R. G. Gonzalez, D. N. Louis, and J. R. Stone Case records of the Massachusetts General Hospital. Case 23-2006. A 36-year-old man with numbness in the right hand and hypertension. N. Engl. J. Med., July 27, 2006; 355(4): 394 - 402. [Full Text] [PDF]

				N. Tang, F. Mack, V. H. Haase, M. C. Simon, and R. S. Johnson pVHL Function Is Essential for Endothelial Extracellular Matrix Deposition. Mol. Cell. Biol., April 1, 2006; 26(7): 2519 - 2530. [Abstract] [Full Text] [PDF]