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In the past year, the VHL protein has come to be appreciated as a regulator of the levels of other proteins in the cell. It teams up with Elongin B, Elongin C, and Cul-2 to form a VHL Complex. This team then sorts proteins and marks certain ones for degradation, in much the same way that a forester would go through a forest and paint X’s on the trees that should be cut down. It’s not just one protein that it is controlling. Scientists have already identified several such proteins. This helps to explain why VHL seems to have such a wide variety of effects. If we think of that forester — cutting down a tall tree brings more light into the forest floor. Cutting down a tree that is too close to another gives the second tree room to grow. We are trying to understand what happens when VHL is working properly, and what doesn’t happen when VHL is not working properly, so that we can discover new ways to intervene and make the end result turn out right.

Dr. William Rigby

Dr. William Rigby, Dartmouth-Hitchcock Medical Center, Dartmouth, Massachusetts, in his project "VHL regulates hnRNP A2 expression," will study one of the ways that the breakdown of VHL function in the cell may lead to cancer only in some kinds of cells. Funding $30,000 from the VHL Family Alliance.

This project will examine the finding that hnRNP A2, an RNA-binding protein, appears to be found in over-supply only in kidney cancer cells that lack the VHL protein. The overexpression of hnRNP A2 has been found in other tumors and may therefore play a role in the development of cancer when the VHL protein is absent. The project will examine the mechanism by which VHL regulates levels of hnRNP A2, and will correlate this finding with the mutations of the VHL gene that are associated with various cancers."

Dr. Maria Czyzyk-Krzeska, University of Cincinnati, Ohio, will be continuing her stody of "VHL Function in Pheochromocytoma." Funding: $30,000 from the VHL Family Alliance.

We are renewing the grant awarded to her last year to study the role of the VHL protein in the creation of a pheochromocytoma. In the work completed to date she has established that pVHL regulates the expression of the hypoxia-inducible tyrosine hydroxylase (TH), an enzyme that controls the amount of catecholamines the body makes. This year’s project will focus on the mechanism by which pVHL regulates the levels of TH, and the influence of cell density on the amount of TH manufactured in the cell.

"The major significance of our preliminary results is that VHL, the gene linked to pheochromocytoma tumors in VHL disease, is also a strong regulator of catecholamine synthesis. Disruption of normal VHL protein function, as in VHL disease, results not only in the pheochromocytoma tumor formation, but also in augmented catecholamine synthesis and release. These results will provide new and unique insights into the understanding of VHL function in the pheochromocytoma tumors and VHL disease."

Dr. Czyzyk-Krzeska and her entire team attended and participated in the Symposium.

Dr. Shahriar Koochekpour, University of Louisiana, New Orleans, working in the laboratory of Dr. Jim Gnarra, will investigate the mechanisms whereby the VHL protein influences the interaction of cells with their surrounding matter (the "extracellular matrix" or ECM) through the so-called fibronectin-integrin system. Funding: $30,000 from the VHL Family Alliance.

The extracellular matrix serves as a fence for cells. It keeps cells organized and working properly. This is done in part through proteins on the surface of cells called integrins. The integrins reach out and touch the ECM proteins and this interaction helps to maintain order. Understanding how cells communicate with their environment is critical because these interactions can regulate the rate at which cells proliferte, and they can also prevent cells from invading other tissues and forming metastases. In cells lacking the VHL protein, this communication is deficient, and cells can grow into a tumor, and eventually invade other tissues and metastasize. This research will build upon the finding of Dr. James Gnarra’s team renal cell carcinoma (RCC) cells lacking pVHL over-produce proteases, proteins that break down the ECM, allowing the cancer cells to escape.

As printed in the VHL Family Forum Research Report 8:5, December 2000. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.