Three articles in this week's issue of Science show the key role of the VHL protein in the life of a cell; we tell its role in the life of the family.

"You don't look sick." A handsome, sturdy young man of 20, Chad looks like he could lift weights with the best of them.

"I'm not sick," Chad replies matter-of-factly, brushing his ash-blond hair across his forehead. "I just have another brain tumor. I wanted to go get it fixed over Thanksgiving, but my mother thinks I should wait for the Christmas holiday." He smiles at his mother, that fond, wry smile that signals that he thinks she is being a little bit overprotective.

"I want him to have the longer time to recuperate before he has to go back to school," his mother adds. "He heals quickly. The last two times he was back in school within ten days. But it's not much longer to wait and he doesn't have symptoms yet."

There is a calm acceptance, that Middle-Western determination that takes life as it comes and makes the best of it. Where most people would be devastated to have even one brain tumor, Chad and his mother have both learned to deal with a series of tumors doled out over a lifetime.

This family is living with von Hippel-Lindau (VHL), a complex syndrome of tumors which may occur in any of a number of places in the body. It is caused by a flaw in the VHL gene, a mistake in the recipe for one of the body's proteins. VHL is one of our tumor-supressor genes, part of the body's natural defense against cancer.In this week's issue of Science there are three articles which announce a breakthrough in our understanding of how cancer works -- the role the VHL protein plays in the life of a cell. This step was made possible by studying what happens when the VHL protein is not there. It was made possible by donations of blood and tumor tissue from hundreds of people with VHL.For families with VHL, this news provides a glimmer of hope that perhaps by the year 2000 there will be a medication to stop, or at least slow down, the growth of new tumors.

Meanwhile, there are a lot of people dealing with a lot of tumors. Without an effective medication, it's a matter of treating one at a time, usually with surgery. "It's almost a matter of how much surgery you can tolerate before you die," says Mark, age 40. "I don't look sick either, but you should see me with my shirt off. Each scar tells the tale of yet another surgery -- fourteen and counting." In Mark's gene there is only one wrong amino acid in the VHL protein -- a single letter wrong in a page of typing.

"What we need," says Joyce Graff of Brookline, Massachusetts, Chairman of the VHL Family Alliance, "-- and what steps like these are slowly moving toward -- is a medication or therapy that will replace the function of the VHL protein, or counteract the bad effects of not having the protein. Understanding the mechanism is the first step to solving the problem." It will take a lot more research -- a lot more time and money -- to find the answer.Families and medical professionals have joined forces in the VHL Family Alliance to share information with one another, provide morale support and work toward furthering our understanding of VHL and all other kinds of cancer.VHL may allow tumors to form in the retinas, brain, spinal cord, kidney, pancreas, or adrenal glands. People who have tumors, especially hemangiomas, in two or more of these areas should ask their physicians about VHL.

Three Articles and commentary, Science, September 8, 1995:

Krumm and Groudine, "Tumor Suppression and Transcription Elongation," 1400-1401

Duan, Linehan, Klausner et al., "Inhibition of Transcription Elongation by the VHL Tumor Suppressor Protein," 1402-1406

Kibel, Kaelin et al., "Binding of the von Hippel-Lindau Tumor Suppressor Protein to Elongin B and C," 3 pp.

Aso, Lane, Conaway & Conaway, "Elongin (SIII): A Multisubunit Regulator of Elongation by RNA Polymerase II," 1439-1446.

For further information about von Hippel-Lindau disease:

For more information about VHL, please contact the VHL Family Alliance, 1-800-767-4VHL, or info@vhl.org.

To interview a VHL family in your local area, Please call Joyce at 1-800-767-4845.

Broadcast-quality video interviews available on request.

Related information from the National Cancer Institute can be found at www.nci.gov

Progress in Understanding the VHL Gene

When the gene was found in June 1993, many people said that that event would greatly promote research on VHL. This year we are seeing the fruits of new labor based on that work. "The identification of tumor suppressor genes whose loss of function results in predisposition to cancer has taken center stage in our attempts to understand human cancer."1 Mutations in these genes are responsible not only for inherited cancer syndromes like VHL, but for similar sporadic cancers too.

In the last several months four teams have published significant strides forward in understanding how the VHL gene works: a team at the U.S. National Cancer Institute (NCI) under Drs. Richard D. Klausner and W. Marston Linehan; one at the Oncology Drug Discovery Department of Bristol-Myers Squibb Research Institute in Princeton, New Jersey, under Dr. Bernd Seizinger; one at the Dana-Farber Cancer Institute in Boston under Dr. William G. Kaelin, Jr., and a team at the Oklahoma Medical Research Foundation under Drs. Ronald and Joan Conaway.

These teams are pursuing the same goal: to identify the specific protein encoded by the VHL gene, understand what it does and how it effects the life of a cell. Once we know how it works and what it does, then various medications and therapies can be proposed to restore the missing function.

The Klausner/Linehan, Seizinger, and Kaelin teams began by creating an antibody to the VHL protein in the bloodstream of a rabbit. When confronted with a foreign substance, the normal function of the immune system is to create an antibody, a neutralizing agent specially formulated to bind with the foreign substance and neutralize its effect. "It's like making a key to fit a lock," says Dr. Jean Whaley of the Seizinger team. The antibody can then be used to determine whether the VHL protein is present, and in what quantities.

The Kaelin team developed antibodies which are capable of recognizing the human VHL protein in cells. Using these antibodies, they confirmed that the human protein contains 213 amino acids. Ironically, the partial gene sequence published in 1993 by Drs. Michael Lerman and Berton Zbar and co-workers contained all the genetic information necessary to encode the complete VHL protein. As predicted from DNA analysis of human kidney cancers, the Kaelin team found that some renal carcinomas fail to produce any normal VHL protein.

At the same time, the NCI and Seizinger teams went on to identify genes in other animals which are similar in molecular structure to the VHL gene, referred to as "homologous" genes. They looked for the same pattern of amino acid sequences in the genetic encoding.

"The isolation and characterization of gene homologues from diverse species often provide important insights into the functional characterization of the respective human protein."2 Discovering what portion of the VHL gene is conserved in evolution, in other animals, can help to indicate which region of the gene might be the most important. The Seizinger team found that the second half of the VHL gene is almost identical to a similar gene in a mouse (mVHL1). As with the human VHL gene, the mouse homologue is widely expressed in different tissue types. The NCI team identified a rat gene which is "88% sequence identical to the 213 amino-acid human VHL gene product."3

The NCI and Kaelin teams are studying the other kinds of proteins the VHL protein tends to bind to. "The finding that the VHL protein forms relatively tight complexes with specific sets of cellular proteins suggests that the identification of these associated proteins will yield clues about the function of VHL and may also lead to identification of other genes critical in growth and/or cell cycle control." Further, these findings promise "that the identification of these VHL-associated proteins will likely lead to understanding the role of this tumor suppressor gene product in the life of the cell."4

The Kaelin team has also conducted experiments using nude mice. Nude mice have no hair; they also have no immune system. When such mice are injected with cells from a human renal cell carcinoma, these cells begin to form tumors. When the healthy VHL protein was reintroduced into the renal cell carcinoma cells, and these cells were subsequently injected into the mice, these cells were inhibited in their ability to form tumors in vivo. (The term in vivo means that it occurs within the body of a living animal.) What tumors did form were consistently smaller. This confirms that the VHL gene is a bona fide tumor suppressor.

In dishes in the lab (in vitro, or literally "in glass"), however, the tumor cells in which VHL function was restored appear to grow normally. "The inability of the VHL protein to suppress cell growth in vitro might, among several possibilities, suggest that VHL protein action depends on cell-cell and/or cell-matrix interactions that occur in vivo. . . [the fact that there are so many new blood vessels in VHL also] suggests a possible role of the VHL protein in the ability of cells to sense changes in the levels of oxygen, and perhaps other nutrients, in their microenvironment."5

In the September 8 issue of Science Magazine, these teams publish the next step in their research.

The Conaway team reported their findings about a substance important in cell growth, called Elongin. This complex of three small proteins A, B, and C is suspected to play a key role in the cycle of cell progression, development, and cell death. All cells must make new proteins every day. Each gene (which is made of DNA) carries the information necessary to construct a particular protein. The gene must, however, first be converted, or transcribed, into RNA which then serves as the actual blueprint for protein synethesis.

The transcription process begins with initiation, then elongation, then a series of other steps. Elongin is the key factor in this elongation process. The VHL protein "binds to Elongin B and C and inhibits Elongin (SIII) activity . . . and raises the possibility that Elongin (SIII) may be an integral component of a transcriptional regulatory network controlled at least in part by the VHL protein."6 The Kaelin lab showed that the portion of the VHL gene that is most important in this process is the very region which is most often mutated in VHL families.7

In the Duan study, the VHL protein was shown to bind tightly and specifically to Elongin B and C, and to inhibit Elongin (SIII) transcriptional activity in the laboratory. These findings show a potentially important network of factors that regulate transcription, in which the VHL protein may play a key role.8

What is clear is the ability of the VHL protein, produced by a healthy VHL gene, to suppress tumor growth. As we learn more about the basic biochemistry of the protein and how it stops tumor cells from growing, it will point the way to possible therapies. We are at the beginning of a very exciting time.

The new results reported in Science "are not just a coup for cancer research. The identification and cloning of the VHL gene and its target Elongin will help to elucidate transcriptional elongation, a key regulatory mechanism. . . .We will now be able to move forward without pause in understanding how transcriptional elongation regulates gene expression, cell growth, and neoplasia."9

Notes: 1. Duan(e) 1402. 2. Gao (a) 743. 3. Duan (b) 6459. 4. Duan (b) 6463. 5. Iliopoulos (c) 824. 6. Kibel (f) 7. Aso (g) 1443. 8. Duan (e) 1402. 9. Krumm (d) 1401. Neoplasia is the spontaneous growth of a tumor from a single aberrant cell, as in VHL.

References: (a) Gao, Whaley, Seizinger et al., "Cloning and Characterization of a Mouse Gene with homology to the human von Hippel-Lindau disease tumor suppressor gene," Cancer Research (Feb. 1995), 55:743-747. (b) Duan, Linehan, Klausner et al., "Characterization of the VHL tumor suppressor gene product," Proc. Natl. Acad. Sci., USA, (July 1995) 92:6459-6463. (c) Iliopoulos, Kibel, Gray and Kaelin, "Tumour suppression by the human von Hippel-Lindau gene product," Nature Medicine (Aug. 1995), 1:822-826. Four articles from Science, September 8, 1995: (d) Krumm and Groudine, "Tumor Suppression and Transcription Elongation," 1400-1401; (e) Duan, Linehan, Klausner et al., "Inhibition of Transcription Elongation by the VHL Tumor Suppressor Protein," 1402-1406; (f) Kibel, Kaelin et al., "Binding of the von Hippel-Lindau Tumor Suppressor Protein to Elongin B and C," 3pp.; (g) Aso, Lane, Conaway & Conaway, "Elongin (SIII): A Multisubunit Regulator of Elongation by RNA Polymerase II, 1439-1446.

How This Puts us Closer to a Realistic Therapy

Steps Toward an Effective Medication

Find the chromosome where the gene is located
Find the gene itself
Determine how the gene functions normally in the cell
Determine how the damage to the gene leads to the manifestations of VHL disease
Find drugs that mimic the role of the VHL protein
Evaluate some of those medications in clinical trials with people with VHL.

A primer regarding the function of the VHL gene

The process of creating RNA from DNA is called transcription.

The process of creating a protein from the RNA template is called translation.

Elongin helps to speed up the transcription process. With a normal VHL gene, and the presence of the VHL protein, the Elongin does its job normally, and the transcription process proceeds normally.

When the VHL gene is mutated and the VHL protein is not there to bind the Elongins and regulate them, the "brakes are off" and cell growth goes out of control.

"This ties together cancer and microbiology in a way they have never been tied before." -- Dr. W. Marston Linehan, National Cancer Institute.

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