Von Hipple Lindau and Ubiquitin

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Figures 1: Ultrasound and CT images. There are cysts in the pancreas and kidneys. There are complex solid masses in both kidneys. There is tumor invasion of the right renal vein and IVC.

Figure 2: Chromosomal location for VHL gene

Von Hippel - Lindau syndrome is a multisystem disease characterized by hemangioblastomas of the cerrebellum, spinal cord, and retina, renal, pancreatic and hepatic cysts, clear cell renal cell carcinoma,endolymphatic sac tumors and pheochromocytoma. Retinal hemangioblastomas may be the first sign of VHL causing visual problems. Cerebellar hemangioblastomas may present with headache, vomiting, and ataxia. Multiple renal cysts are common in VHL syndrome. Renal cell carcinoma is the leading cause of mortality. Usually this is the clear cell type developing either within a cyst or in the surrounding parenchyma. Pheochromocytomas can be asymptomatic, but may cause hypertension. Endolymphatic sac tumors can cause hearing loss.

Changes in patterns of gene expression can result from relatively small changes in the concentrations of sequence - specific transcription factors. Hypoxia-inducible factor-1 (HIF 1) is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. (HIF 1 location 14q21-24). VHL encodes a ligase that promotes Ubiquitin degradation of the alpha subunits of the hypoxia-inducible transcription factors HIF 1, HIF 2, and HIF 3, leading to their degradation by the proteasome. Consequently, renal carcinomas with mutations in VHL have high steady-state levels of HIF expression. Functional studies show that HIF is sufficient for transformation caused by loss of VHL, thereby establishing HIF as the primary oncogenic driver in kidney cancers.

Loss of VHL sensitizes cancer cells to the rapomycin (mTOR) inhibitor CCI - 779 in vitro and in mouse models. Growth arrest caused by CCI - 779 correlated with a block in translation of mRNA encoding HIF 1A. VHL - deficient tumors showed increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR - dependent manner. The findings provided preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggested that FDG - PET scans may have use as a pharmacodynamic marker in this setting.

The highly vascular tumors associated with von Hippel - Lindau syndrome overproduce angiogenic peptides such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). VEGF mRNA is upregulated in von Hippel - Lindau syndrome-associated tumors.

VHL and transcription factor Sp1 directly interact with an inhibitory effect on Sp 1, suggesting that loss of transcription factor Sp1 inhibition may be important in the pathogenesis of von Hippel - Lindau syndrome and renal cell carcinoma. 12q13.1 is the most probable location of the SP 1 gene.

Reference: OMIM 608537

Addendum: Very interesting article by Prassad et al related to this case in Radiology for Nov-Dec 2006 with interesting commentary by Dr Peter L. Choyke