The VHL tumour-suppressor gene paradigm

doi:10.1016/S0168-9525(98)01558-3

Trends in Genetics

Volume 14, Issue 10, 1 October 1998, Pages 423-426

https://doi.org/10.1016/S0168-9525(98)01558-3 Get rights and content

Abstract

The VHL tumour-suppressor gene (TSG) has a critical `gatekeeper' role in regulating growth and differentiation of human kidney cells, and inactivation of the VHL gene is the most frequent genetic event in human kidney cancer. There are many similarities between the genetics of the VHL and retinoblastoma TSGs, but the VHL tumourigenesis model is more complex. Here, we examine the current knowledge of the genetics and functional aspects of the VHL TSG, and emphasize how the VHL gene provides a paradigm that illustrates many aspects of TSG biology.

Section snippets

The VHL gene and VHL disease

The 213 amino acid coding sequence of the VHL gene is represented in three exons contained within a 20 kb region at chromosome 3p25 (Ref. [3]). Germline mutations cause VHL disease (Fig. 1), a dominantly inherited disorder characterized by variable expression and susceptibility to a variety of malignant and benign tumours[4]. The VHL TSG mRNA is expressed widely during embryogenesis and in adult tissues5, 6. In particular, tissue-specific differences in VHL mRNA or protein (pVHL) production do

The VHL TSG and sporadic cancers

As for inherited retinoblastoma, tumours from VHL patients characteristically demonstrate loss of the wild-type allele, consistent with the classical two-hit model of tumourigenesis[14]. RCC accounts for about 2% of all cancers and the most common subtype is described as `clear cell' according to the microscopic appearance of the tumour cells. VHL disease accounts for less than 2% of all cases of kidney cancer, but somatic VHL gene mutations are found in most nonfamilial RCC15, 16. This is

pVHL regulates angiogenesis

Angiogenesis is critical for normal development and for tumourigenesis. VHL-associated neoplasms, such as haemangioblastoma and RCC, are notable for their vascularity [retinal haemangioblastomas are sometimes referred to as angiomas (Fig. 2)]. These tumours produce high levels of vascular endothelial growth factor (VEGF). Although overproduction of VEGF mRNA is a feature of many human cancers, this has been primarily linked to hypoxia. However, RCCs lacking functional pVHL produce high levels

The VHL protein product

The full-length 213 amino acid VHL protein (VHL_L) migrates with an apparent molecular weight of ∼28–30 kDa, but a second form of VHL protein (VHL_S), generated by translation initiation at an internal methionine located at residue 54, migrates with an apparent molecular weight of 19 kDa. The primary sequence of pVHL is not highly similar to that of any known protein and did not provide any clues to the possible function. To elucidate possible functions, several groups sought to identify

The VHL TSG: an evolving paradigm

This review has highlighted some of the similarities between the retinoblastoma TSG paradigm and VHL disease. In both cases, the characterization of a gene accounting for a rare familial cancer syndrome has led to the identification of a critical gatekeeper gene that is frequently mutated in more common sporadic cancers. RB1 and VHL function as recessive TSGs and, at the time of their identification, the possible biochemical functions of the RB1 and VHL protein products were unknown. The

Acknowledgements

We apologize to those investigators whose work we were unable to cite because of lack of space. We thank Farida Latif, and members of the Kaelin and Maher Labs for helpful suggestions and criticisms. Hartmut Neumann provided part of Fig. 1.

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Trends in Genetics

The VHL tumour-suppressor gene paradigm

Abstract

Section snippets

The VHL gene and VHL disease

The VHL TSG and sporadic cancers

pVHL regulates angiogenesis

The VHL protein product

The VHL TSG: an evolving paradigm

Acknowledgements

Hum. Pathol.

Eur. J. Cancer

Cell

J. Biol. Chem.

Trends Genet.

Cell

Biochim. Biophys. Acta

Cell

Science

Proc. Natl. Acad. Sci. U. S. A.

Science

Medicine

Hum. Mol. Genet.

Q. J. Med.

Hum. Genet.

Hum. Mutat.

Hum. Mol. Genet.

Hum. Mutat.

J. Am. Med. Assoc.

Hum. Genet.

Hum. Mol. Genet.

Nat. Genet.