Role Found for VHL Tumor Suppressor Gene

The following is the text of a statement prepared by the NCI Press Office (301-496-6641), dated September 15, 1995.

Researchers at the National Institutes of Health (NIH) have made a major step forward in understanding the normal function of a tumor suppressor gene that plays a critical role in kidney cancer and the hereditary disorder known as von Hippel-Lindau (VHL) disease. They found that the VHL tumor suppressor protein normally associates with another protein, called Elongin, which is known to play an important part in cellular transcription -- the process of making an RNA copy of a gene before making its protein product.

VHL is a member of a group of genes called tumor suppressor genes, including BRCA1, retinoblastoma, p53, and others, because people with mutations in these genes develop tumors more frequently than those with a normal copy of the gene. Patients with von Hippel-Lindau disease have a specific defect in the VHL gene that predisposes them to a variety of benign and malignant tumors in a number of organs, including kidney, retina, central nervous system, pancreas, and adrenal gland. Abnormalities in the VHL gene have also been detected in a high percentage of tumors from patients with a certain form of kidney cancer.

In a study published in the September 8 issue of Science, the NIH group, led by Richard Klausner, M.D., then at the National Institute of Child Health and Human Development and now director of National Cancer Institute (NCI) and Marston Linehan, M.D., of NCI's Surgery Branch found that the VHL protein normally does not associate with the entire Elongin protein, but with only two of its three parts.

Elongin, a large nuclear protein, discovered in 1993 in the laboratory of Joan Weliky Conaway, Ph.D., and Ronald C. Conaway, Ph.D., biochemists from the Oklahoma Medical Research Foundation, Oklahoma City, is made up of three subunits, named A, B, and C. When the three subunits bind to each other in a cell, they function as a single protein to increase the rate of transcription; each subunit contributes to the function of the whole protein.

NCI's study shows that the two cellular proteins that bind consistently to the normal VHL protein are Elongin B and C. Further experiments carried out in collaboration with the Oklahoma group showed that, in the test tube, VHL protein competed with Elongin A for the B and C subunits, and that VHL blocked Elongin's ability to increase transcription. Therefore, it is likely that when normal VHL protein is present in a living cell, it prevents Elongin A protein from associating with B & C subunits, inhibiting Elongin's function. This hypothesis is supported by fact that the only portion of the VHL protein that is similar to any other protein is a stretch of 13 amino acids also found in Elongin A.

These results are a major advance in relating the VHL protein to a specific cellular process. Although the VHL gene was cloned in NCI labs in 1993, the predicted amino acid sequence gave no clues about its function because it was unlike any known protein. However, in the July issue of the Proceedings of the National Academy of Sciences, NCI's group led by Klausner and Linehan, reported finding the two VHL-binding proteins, but identified them only by size.

"Our previous studies of the VHL gene led us to an understanding of the genetic basis of kidney cancer and VHL disease. This work takes us from clinical medicine to understanding specific molecular events that may lead to cancer," said Linehan.

One of the surprising aspects of the findings involves looking at a part of the transcription process not normally studied. During transcription, cellular proteins can intervene in one of three stages -- initiation, elongation, and termination. The Conaway team and others have for many years focused on proteins that control transcription initiation, and on ways these early transcription proteins can influence faulty gene expression in human disease, including cancer. The middle stage of transcription -- elongation, the addition of RNA subunits to make the RNA transcript longer -- has been largely ignored. Elongin is one of a handful of proteins shown by the Conaway group to affect the rate of transcription elongation.

The Conaways were delighted to be contacted by NCI's researchers for help in identifying Elongin B whose sequence the Conaways knew, but had not yet published.

"We've been working hard for many years on proteins that regulate transcription at both initiation and elongation. The discovery of the connection between VHL and Elongin is one of those wonderful occasions we all wait for when basic scientific research and medically-oriented research intersect, and lead to much more rapid progress than could have been made with either approach alone," said Joan Conaway.

These studies also suggest a mechanism by which a mutated VHL gene could enhance tumor growth and cause disease. In the past, studies with von Hippel- Lindau disorder and kidney cancer patients have shown that certain parts of the VHL gene (and, therefore its protein) are more frequently mutated than others. The Klausner and Linehan group show in their study that these VHL mutant proteins lose their ability to bind to the Elongin protein subunits, suggesting that the same process may happen in the disease.

Advocates for families with von Hippel-Lindau disorder, see the research as a step closer towards devising a rational therapy for treating the disease. One approach might be to devise drugs that can restore the ability of mutated VHL protein to inhibit Elongin -- create synthetic Elongin inhibitors. (About 7,000 people in the United States have been diagnosed with von Hippel-Lindau disease, and between 15,000 and 20,000 people in the United States are diagnosed each year with kidney cancer associated with mutations of the VHL gene.)

For now, future studies will attempt to define the parts of Elongin B and C proteins that combine with VHL and Elongin A, to study the factors that control the amounts of VHL protein in the cell, and to identify other VHL- associated proteins.

The precise mechanism by which transcription elongation controls the expression of specific genes, regulates normal cellular growth, or prevents tumor formation is not known. But understanding that the regulation of elongation may be involved in the disease process of a tumor suppressor gene represents a major step forward.

"The identification of what may be a new tumor suppressor gene pathway will simultaneously have implications for understanding basic biology and the essential steps that transform a normal cell to a cancer cell," said Klausner. "I will be surprised if this pathway is limited to von Hippel-Lindau disease and kidney cancer."

Date Last Modified: 11/95