VARI identifies potential drug target

September 27, 2008
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Researchers at Van Andel Research Institute in Grand Rapids have determined the molecular structure of a nuclear receptor named COUP-TFII, and the finding could provide the basis for development of a targeted drug treatment for diseases related to heart and blood vessel development, human embryonic development and female infertility.

A nuclear receptor regulates the expression of specific genes inside cells. Unlike other classes of receptors, a nuclear receptor can bind directly to DNA and act as a “transcription factor” — sometimes called sequence-specific DNA binding factors — which play key roles in embryonic development and cellular metabolism.

VARI researchers used X-ray crystallography to determine the molecular structure of COUP-TFII. When a crystal is exposed to X-rays, its three-dimensional arrangement of atoms can be exploited to determine molecular identity and structure. The greater level of detail of molecular structure can aid drug developers in engineering a drug that more perfectly fits the receptor, thus rendering it more potent. It can also aid in manipulating drugs to produce fewer side effects. 

“The knowledge of how COUP-TFII functions at the molecular level is very limited, and our structural studies provide a critical piece of information for understanding how COUP-TFII functions,” explained Eric Xu, Ph.D., the distinguished scientific investigator who heads VARI’s Laboratory for Structural Science. “Not only does the structural information provide a basis for drug design in any diseases that COUP-TFII plays a role in, but it also can provide insight into the entire subfamily of receptors that COUP-TFII belongs to, which could have implications for additional associated diseases.”

VARI researchers found DNA changes specific to type 1 and 2 papillary RCC, sarcomatoid RCC and clear cell RCC — with or without a mutation of the VHL gene, a tumor suppressor gene that prevents cells from growing and dividing too rapidly or in an uncontrolled manner.

Researchers also found that the COUP-TFII receptor is activated by retinoic acid, a form of Vitamin A. That finding itself is a “first” because until now, no one had identified the signal triggering molecules, or ligands, that activate COUP-TFII. COUP-TFII was considered an “orphan” nuclear receptor prior to the VARI study because it was not known whether it actually could be regulated by a ligand. Vitamin A comes in many forms in the human body and plays many important roles in the development of the heart, liver and brain, Xu explained. In identifying that retinoic acid can activate COUP-TFII, VARI researchers basically established that COUP-TFII is a ligand-regulated nuclear receptor — in this case a retinoic acid-activated receptor — which suggests that COUP-TFII acts as a key mediator of the vitamin A signaling pathway, he said.

That raises a new question, Xu said: What is the endogenous ligand for COUP-TFII? The finding also paves a way to turn COUP-TFII activity on or off for therapeutical intervention, he observed. Xu said in the next phase of the study, his lab wants to identify the endogenous ligand for CORP-TFII because such a study could open a whole field of biology related to vitamin A and COUP-TFII.

But there’s more.

Lead author of the study, Schoen Kruse, Ph.D., said the findings could also extend to cancer therapy.

“Since COUP-TFII plays a role in embryonic blood vessel development, it might play a similar role in tumors and cancer growth,” explained Kruse, a former postdoctoral fellow at VARI and now an assistant professor in the department of pharmacology at Rocky Vista University, College of Osteopathic Medicine. “Formation of new blood supply in tumors is a stepping stone in the ability of cancers to grow and metastasize within the body.”

The study was initiated in 2003 and the findings were published in the Sept. 16 issue of PloS Biology. Though researchers in different VARI labs ofen confer on ongoing projects, that was not the case in this study. Only researchers in the Laboratory of Structural Sciences were involved, but they did receive an assist from VARI’s Mass Spectrometry Core Services Laboratory.

The majority of funding for this particular study was in the form of a grant from the National Institutes of Health, which will support Xu and his team’s structural studies until June 2010.

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