ORIGINAL ARTICLE

Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter

M Zatyka¹, C Morrissey¹, I Kuzmin², M I Lerman³, F Latif¹, F M Richards¹, E R Maher¹

¹ Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK
² Intramural Research Support Program, SAIC-Frederick Inc, Frederick, MD 21702, USA
³ Laboratory of Immunobiology, NCI-Frederick, MD 21702, USA

Correspondence to:
Correspondence to:
Professor E R Maher, Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Birmingham B15 2TT, UK;
ermaher{at}hgmp.mrc.ac.uk

The VHL gatekeeper tumour suppressor gene is inactivated in the familial cancer syndrome von Hippel-Lindau disease and in most sporadic clear cell renal cell carcinomas. Recently the VHL gene product has been identified as a specific component of a SCF-like complex, which regulates proteolytic degradation of the hypoxia inducible transcription factors HIF-1 and HIF-2. pVHL is critical for normal development and mRNA expression studies suggest a role in nephrogenesis. Despite the importance of VHL in oncogenesis and development, little is known about the regulation of VHL expression. To investigate VHL promoter activity, we performed comparative sequence analysis of human, primate, and rodent 5‘ VHL sequences. We then proceeded to deletion analysis of regions showing significant evolutionary conservation between human and rat promoter sequences, and defined two positive and one negative regulatory regions. Analysis of specific putative transcription factor binding sites identified a functional Sp1 site, which was shown to be a regulatory element. Overlapping Sp1/AP2 sites were also identified and candidate E2F1 binding sites evaluated. Three binding sites for as yet unidentified transcription factors were mapped also. These investigations provide a basis for elucidating the regulation of VHL expression in development, the molecular pathology of epigenetic silencing of VHL in tumourigenesis, and suggest a possible link between Sp1, VHL, and nephrogenesis.

Keywords: von Hippel-Lindau disease; VHL tumour suppressor gene promoter; sequence analysis

Abbreviations: VHL, von Hippel-Lindau disease; TSG, tumour suppressor gene; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; CR; conserved region

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Tan, S. H., Pal, M., Tan, M. J., Wong, M. H. L., Tam, F. U., Teo, J. W. T., Chong, H. C., Tan, C. K., Goh, Y. Y., Tang, M. B. Y., Cheung, P. C. F., Tan, N. S. (2009). Regulation of Cell Proliferation and Migration by TAK1 via Transcriptional Control of von Hippel-Lindau Tumor Suppressor. J. Biol. Chem. 284: 18047-18058 [Abstract] [Full Text]  
• Phillips, R. J., Mestas, J., Gharaee-Kermani, M., Burdick, M. D., Sica, A., Belperio, J. A., Keane, M. P., Strieter, R. M. (2005). Epidermal Growth Factor and Hypoxia-induced Expression of CXC Chemokine Receptor 4 on Non-small Cell Lung Cancer Cells Is Regulated by the Phosphatidylinositol 3-Kinase/PTEN/AKT/Mammalian Target of Rapamycin Signaling Pathway and Activation of Hypoxia Inducible Factor-1{alpha}. J. Biol. Chem. 280: 22473-22481 [Abstract] [Full Text]  
• Sufan, R. I., Jewett, M. A. S., Ohh, M. (2004). The role of von Hippel-Lindau tumor suppressor protein and hypoxia in renal clear cell carcinoma. Am. J. Physiol. Renal Physiol. 287: F1-F6 [Abstract] [Full Text]