Scientists at the Oklahoma Medical Research Foundation, whose previous research on the tumor-suppressing von Hippel-Lindau gene was hailed as a “coup for cancer research” by the journal Science, have now linked their discoveries to a general mechanism for controlling cell growth. Defects in the von Hippel-Lindau gene are associated with most cases of clear-cell renal carcinoma, the most common form of kidney cancer, and with von Hippel-Lindau disease, a rare genetic condition that predisposes affected people to a variety of cancers and to tumors of the eye, brain, spinal cord, pancreas, liver or adrenal gland.
In two research papers published today in Science, Drs. Joan and Ronald Conaway of OMRF’s Program in Molecular and Cell Biology and an interdisciplinary team of scientists including Drs. Takumi Kamura and Michael Conrad of OMRF, Drs. Wade Harper and Stephen Elledge and their colleagues at Baylor College of Medicine, and Dr. William Kaelin and colleagues of the Dana-Farber Cancer Institute at Harvard Medical School, reported discovery of a new protein, Rbx1, that is a part of the von Hippel-Lindau, or VHL, tumor suppressor machinery. Remarkably, Rbx1 is also found as a critical component of the machinery that controls cell growth and division by targeting important regulatory proteins for destruction.
“An exciting hypothesis is that, in its normal form, VHL works together with Rbx1 to prevent the cell from accumulating proteins that trigger uncontrolled cell proliferation. But a mutation in the gene that produces VHL can cause cancer by interfering with the cell’s ability to destroy the trigger proteins, leading to runaway cell growth,” said Joan Conaway, Howard Hughes Medical Institute investigator at OMRF.
Notes Ron Conaway, “Not surprisingly, the mechanisms that regulate protein destruction are turning out to be every bit as complicated and every bit as important as those that regulate protein synthesis. The discovery of the link between VHL, Rbx1, and the protein destruction machinery should help researchers identify the specific trigger proteins targeted by VHL and may lead to new approaches to cancer prevention and treatment.”
In 1993 the Conaways discovered and isolated the Elongins as proteins that help to control the mechanism that turns genes, including cancer genes, on or off. In 1995 they collaborated with Drs. Richard Klausner and Marston Linehan of the National Institutes of Health (NIH) to demonstrate that the Elongins function in cells with the VHL tumor suppressor protein to prevent cancer.
“These findings represent a significant advance in our understanding of the function of the VHL gene and how damage to this gene leads to the manifestations in patients that we know of as cancer,” said W. Marston Linehan, M.D., Chief of the Urologic Oncology Branch at the National Cancer Institute. “We strongly feel that it is work such as this that will one day play a major role in the development of effective forms of therapy for patients with kidney cancer.”
The Conaways have been involved in basic biomedical research on gene expression since the mid-1980s, when they were at the DNAX Research Institute and Stanford University School of Medicine. In 1997, the couple received the Amgen Award from the American Society of Biochemistry and Molecular Biology, a prestigious award reserved for young investigators who have “had significant achievements in the application of biochemistry and molecular biology to the understanding of disease.”
“Joan and Ron Conaway’s young careers have been marked by great promise resulting in major scientific contributions,” said J. Donald Capra, M.D., OMRF president. “It is also a great source of pride that Joan Conaway is a Howard Hughes Medical Institute investigator, one of only two in the state of Oklahoma, both of whom are at OMRF.”
The Conaways’ research is supported by the Howard Hughes Medical Institute, the National Institutes of Health, and by funds provided to OMRF by the H.A. and Mary K. Chapman Charitable Trust of Tulsa, OK.
