Von Hippel-Lindau tumor-suppressor gene

Pause, A., et al.. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci USA, 1997, 94(6), 2156-61. 

Krieg M, Haas R, Branch H, Acker T, Flamme I, Plate KH. Up-regulation of hypoxia-inducible factors HIE-1 alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 2000 19 5435-5443. 

Na X, Wu G, Ryan CK et al. (2003) Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas. J Urol 170 588-592... 

Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP. The von Hippel-Lindau tumor suppressor gene product interacts with Spl to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 1997 17 5629-5639. 

Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993, 260, 1317-20. 

Recent studies have demonstrated that overexpression of HDACl represses the tumor suppressors, p53 and von Hippel-Lindau (VHL), but induces the hypoxia-responsive genes, hypoxia inducible factor alpha (HIF-la) and vascular endothelial growth factor (VEGF) and increases angiogenesis. Conversely, HDAC inhibitors derepress the tumor suppressors, p53 and VHL, and repress HIF-la and VEGF [68, 69]. 

Carlo H, Schwarz K, Jorch N, Kyank U, Petrides PE, Schneider DT, Uhle R, Debatin KM, Kohne E. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica 2005 90 19-24. 

Vortmeyer AO, Lubensky lA, Fogt F, et ak Allelic deletion and mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in pancreatic microcystic adenomas. Am J Pathol. 1997 151 951-956. 

Von Hippel-Lindau disease (VHL) is an autosomal dominant condition secondary to an alteration in a tumor suppressor gene on chromosome 3. It has incomplete penetrance and is characterized by hemangioblastomas in the retina, CNS, renal cell carcinoma, endolymphatic sac tumors, pheochro-mocytomas, papillary cystadenoma of the epididymis, angiomas of the liver and kidney, cysts of the liver, kidney and epididymis, and pulmonary arteriovenous shunts (Fig. 4.18a-c). In the pancreas, VHL may have multiple presentations, the most common being the presence of multiple small pancreatic cysts with calcifications in 40% of cases. Serous cystad-enomas, solid nonfunctional islet cell tumors, and adenocarcinoma are less common (Richard et al. 2004). 

A significant step toward understanding how HIF destruction is regulated was the recognition of the critical role of the von Hippel-Lindau (VHL) tumor suppressor protein (32). The VHL gene is situated at 3p25 and was originally cloned in 1993 as... 

Latif F, Tory K, Gnarra J, Yao M, Duh F-M, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke R Walther MM, Weng Y, Duan D-SR, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumakov 1, Cohen D, Chinault AC, Maher ER, Linehan WM, Zbar B, Lerman MI. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993 260 1317-1320. 

Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated fi om an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci USA 1998 95 8817-8822. 

Tsuchiya H, Iseda T, Hino O. Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau (VHL) tumor suppressor gene product. Cancer Res 1996 56 2881-2885. 

Renal tumors can occur as part of complex genetic diseases (Table 3.7). Tumors are major manifestations in the two forms of tuberous sclerosis and the von Hippel-Lindau syndrome. The responsible genes are tumor suppressor genes. The two step hypothesis of Knudson gives an explanation for the great clinical variability. 

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