TSRI Team Solves Structure of Important Tumor Growth Protein—A Target for Cancer Therapy

By Jason Socrates Bardi

A team of scientists at The Scripps Research Institute (TSRI) have solved a structure of a protein that is crucial for cancer tumor growth. Blocking this protein has already proven to be an effective way of stopping tumor growth in animal models, and the unforeseen molecular details revealed by the structure are like a roadmap for the development of future anti-cancer therapeutics.

In the April 16 issue of the journal Proceedings of the National Academy of Sciences, a team led by investigators Peter Wright and Jane Dyson solved the structure of the important "alpha" domain of an activator protein called hypoxia inducing factor (HIF-1) in complex with its "coactivator" protein called CBP.

"HIF-1 is a potential target for drugs that will stop tumor growth," says Wright, who is Cecil H. and Ida M. Green Investigator in Medical Research and Chairman of the Department of Molecular Biology at TSRI, "because it is extremely important for angiogenesis."

Angiogenesis, the process where blood vessels are formed and differentiated, is the body's way of responding to hypoxia, a deficiency of oxygen reaching the body's tissues. Hypoxia and angiogenesis play major roles in the pathology of cancer, heart disease, and stroke.

Normally, when cells are starved of oxygen, they exhibit a hypoxic response—turning on genes that induce angiogenesis and bringing more oxygen-rich blood to cells that need it. This increased blood supply allows the cell to survive oxygen deprivation, and HIF-1/CBP is like the valve that turns on the flow.

However, angiogenesis can also be insidiously hijacked by the blood-greedy cells of a cancer tumor. In order for a tumor to grow, its cells need to increase their blood supply. They accomplish this by turning on HIF-1/CBP and telling the body to make new blood vessels.

Once these new blood vessels are made, they bring vital oxygen to the tumor and can even allow cancerous cells to escape into the bloodstream and migrate to another tissue (the process known as metastasis).

Blocking angiogenesis can regress tumors, and scientists are particularly interested in finding ways of accomplishing this, with the goal of identifying specific drugs that might produce much milder side effects than general chemotherapy. And one of the best starting points for designing specific drugs is to thoroughly understand the structures and mechanisms of the important molecular players involved.

"The HIF-1a/CBP structure gives us insight into the mechanism by which the two proteins recognize each other and how they are regulated," says Wright.

Significantly, the structure reveals, for the first time, the basis of the exquisite specificity involved in the interaction between Hif-1a and CBP—the addition of a hydroxy (OH) group to a single asparagine amino acid within the contact region can completely disrupt the complex.

"This [information] provides a starting point for the design of antitumor agents," says Maria Martinez-Yamout, who is one of the lead authors on the paper. These agents, says Martinez-Yamout would, for example, mimic the effect of the hydroxy addition and block the activity of HIF-1 in cancerous cells.

And, lacking oxygen, the cancerous cells would not be able to continue dividing and tumor growth would stop.

The research article "Structural basis for Hif-1a/CBP recognition in the cellular hypoxic response" is authored by Sonja A. Dames, Maria Martinez-Yamout, Roberto N. De Guzman, H. Jane Dyson, and Peter E. Wright.

The research was funded by the National Institutes of Health and the Skaggs Institute for Chemical Biology.




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This ribbon diagram represents a single NMR structure of the Hif-1a:TAZ1 complex that the team solved (TAZ1 is the zinc-binding element of CBP). The amino terminus of the rust-colored Hif-1a and the carboxy and amino termini of the blue TAZ1 are labeled. The zinc ions are represented as white spheres, and the side chains of the cysteine and histidine ligands are shown in yellow and blue, respectively.