Researchers link cancer suppressor to polycystic kidney disease control

April 26, 2001

Researchers at the CIIT Centers for Health Research and the University of Texas M.D. Anderson Cancer Center have discovered that a tumor suppressor gene that inhibits kidney cancer also controls a major gene for polycystic kidney disease. The findings provide insights that may lead to new therapies. The research team also included collaborators from Genzyme Genetics and the Mayo Clinic.

"The biological behavior of the renal cysts that develop in patients with polycystic kidney disease shares many similarities with kidney cancer, and suggested to us that there could be a link between these two diseases," said Professor Cheryl Walker of the University of Texas MD Anderson Cancer Center. "The finding that the same tumor suppressor gene can control both polycystic kidney disease and tumor development establishes this link for the first time, and proves that a connection exists between polycystic kidney disease and kidney cancer at the molecular level."

More prevalent than better-known diseases such as cystic fibrosis or sickle cell anemia, autosomal dominant polycystic kidney disease or ADPKD is the most common lethal genetic disease in humans. It is a leading cause of kidney failure, end-stage renal disease, and the need for dialysis.

The findings are published in and featured on the cover of the April 26th issue of the journal Molecular Cell. (Kleymenova, et. al. Tuberin-dependent membrane localization of polycistin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene.)

Professor Walker and Dr. Jeffrey Everitt developed a rat model carrying a defective tuberous sclerosis 2 (TSC2) tumor suppressor gene at CIIT in the early 1990s to study kidney cancer (Walker, et al Science, 1992). In 1997, Dr. Kleymenova, with the other collaborators, continued with the same model searching for genetic defects causing severe polycystic kidney disease in these rats. The researchers found that the TSC2 gene also controlled the function of PKD1, the major gene for ADPKD. They discovered that the protein produced by the TSC2 gene - called tuberin - is necessary for the proper function of PKD1 gene protein, polycystin-1.

"These findings were possible because of the advances in molecular genetics over the last ten years," said Dr. Elena Kleymenova, a molecular biologist at CIIT. "Although animals with severe polycystic kidney disease were first identified at CIIT in the '90s, our discovery could not be made until the TSC2 and PKD1 genes had been cloned and characterized."

Researchers found that Eker rats - which cannot produce tuberin - contracted the most severe form of polycystic kidney disease. If a kidney cell lacks tuberin, then it can't transport polycystin-1 to the cell membrane where polycystin-1 is needed for normal kidney cell function. However, when the team introduced tuberin into Eker rat kidney cells, polycystin-1 returned to the cell membrane.

Significantly, the study shows a link between the pathways involved in tumor development and cyst development in the kidney, enabling researchers to use information about how cancer develops in the kidney to preventing and treating polycystic kidney disease.

"Because tuberin can regulate the function of polycystin-1, " says Walker, "controlling tuberin expression may be able to limit the severity of polycystic kidney disease in humans, making it a potential therapeutic target." These results may prompt additional efforts to look for defects in the TSC2 gene in ADPKD and contribute to a search for a cure for renal cysts.
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For more information on polycystic kidney disease and tuberous sclerosis contact: PKD Foundation, 1-800-PKD-CURE; pkdcure@pkdcure.org (www.pkdcure.org) and the Tuberous Sclerosis Alliance, 1-800-225-6872; beth.michaels@tsalliance.org.

The CIIT Centers for Health Research is a scientifically independent research institute, supported by the American Chemistry Council as well as government and independent grants. Its research is published in peer-reviewed journals.

The Hamner Institutes for Health

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