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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