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Research Report

by Myriam Gorospe, Ph.D., Director of Research

Nine VHL research proposals were submitted to the VHLFA to receive funding this year. It is a remarkably high number of grants, compared with those received in the past several years: five proposals were submitted in 2000, three proposals in 1999, and two each in 1998 and 1997.

Most of this year’s grants were of outstanding quality, however, the VHLFA has limited funds and was only able to award four of them (up from three grants funded in 2000, three in 1999, two in 1998 and two in 1997. See Figure1)

This year nine grants were submitted, and only four were funded.
Figure 1: Comparing the number of grants funded to the number of grants received.

Two of this year’s awards went to investigators who were applying for a second year of grant support.

Dr. Shahriar Koochekpour is at the Louisiana State University, in New Orleans, Louisiana. His proposal (‘VHL-regulation of Fibronectin-integrin signaling’) addresses highly relevant questions regarding the function of the VHL protein (pVHL) in the cell. During the past year, funding by the VHLFA allowed Dr. Koochekpour to demonstrate that pVHL influences the interaction of cells with their external environment (the so-called extracellular matrix). He showed that pVHL influences the expression of integrins, proteins tightly linked to the communication of the cell and the extracellular environment. For an additional year of funding (2001-2002), the investigator proposes to characterize how VHL influences integrin function and integrin-associated signaling pathways, and, in turn, cell migration and invasion. He further proposes to investigate pVHL’s influence on the expression of enzymes (proteases) involved in the remodeling of the extracellular matrix. Through these studies, he seeks to gain a better understanding of how pVHL affects the proliferation, differentiation, invasiveness, and metastasis of kidney cancer cells, all pivotal questions in VHL disease.

Dr. William Rigby is at Dartmouth College, in Lebanon, New Hapmshire. His clear-cut, focused proposal is entitled ‘The von Hippel-Lindau gene regulates hnRNP A2 expression: A mechanism for the post-transcriptional regulation of hypoxia-inducible genes’. Dr. Rigby’s long-term goal is to address another very important question in the fields of VHL and kidney cancer: how does pVHL influence the expression of other cellular genes? During the first year of funding, this investigator has established that a special protein named hnRNP A2 is overexpressed in pVHL-deficient cells. HnRNP A2 is, in turn, capable of influencing the expression of other important cellular proteins. These observations were written up in a manuscript that was recently submitted to a prestigious biomedical journal. Over the coming year, Dr. Rigby proposes to establish whether pVHL-mediated regulation of hnRNP A2 contributes to the regulation of the expression of genes important for the growth and proliferation of kidney cancer cells. The ultimate goal of his research is to identify the protein targets of pVHL that influence tumorigenesis in order to design improved therapies to manage VHL disease.

The other two awardees will receive funding for the first time.

Dr. Ehud Gazit, at Tel-Aviv University (Israel), submitted his grant entitled ‘The Role of Protein Folding and Stability in the VHL Syndrome’. Dr. Gazit plans to investigate the folding, stability, and subcellular localization on wild-type pVHL, as well as those of various mutant pVHL associated with either type I VHL (characterized by the absence of pheochromocytoma) or type II VHL (where pheochromocytoma occurs). His studies are based on the hypothesis that the VHL mutations leading to type I VHL (large deletions and nonsense mutations) generally lead to alterations in protein folding and stability. By contrast, mutations leading to the type II VHL syndrome seem to affect mostly pVHL’s ability to interact with other proteins. Preliminary results assessed the stability of pVHL protein in response to changes in temperature. The Principal Investigator (PI) proposes to investigate whether chemical chaperones or specific peptides can modulate the stability and folding of the mutant VHL proteins. This is a very promising direction for individuals with the VHL syndrome.

Dr. Robert J. Duronio’s grant is entitled ‘Analysis of Drosophila Rocs, RING Finger Subunits of E3 Ubiquitin Ligase Complexes’. This investigator, from the University of North Carolina, Chapel Hill, proposes to use a very powerful genetic system (the fruit fly) to study the function of pVHL as part of a group of proteins named ‘E3-ubiquitin ligase’. pVHL’s role within the E3-ubiquitin ligase is often compared to that of a ‘garbage collector’. Its purpose in the cell is to eliminate certain cellular proteins that are important for cellular growth and proliferation. Overall, this outstanding proposal is likely to yield high-quality results and to increase considerably our understanding of the VHL tumor suppressor protein and the pVHL-containing E3-ubiquitin ligase complex. This grant proposal is highly relevant to the objectives of the VHL Family Alliance.

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As printed in the VHL Family Forum 9:4, Annual Report 2001. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.

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