Aug. 24, 2007 Most of us think of disease as the failure of an organ or the breach of some critical fortress in the body's defense system. But for many ailments, including cancer and diabetes, disease begins with an even more fundamental error: the failure of genes to turn on and off when they should.
Hoping to understand and eventually help correct such errors, University of Michigan researcher Anna Mapp and coworkers are developing molecules that mimic natural regulators of gene expression. In their latest work, published online Aug. 11 in the Journal of the American Chemical Society, Mapp's group shows that a small molecule they developed is able to turn on genes in living cells.
Molecules that can prompt genes to be active are called transcriptional activators because they influence transcription—the first step in the process through which instructions coded in genes are used to produce proteins. Both natural transcriptional activators and their artificial counterparts typically have two essential parts: a DNA-binding domain that homes in on the specific gene to be regulated, and an activation domain that attaches itself to the cell's machinery and spurs the gene into action.
In earlier work, Mapp's team showed that the artificial activation domains they developed were as effective as a natural activation domain in turning on genes, but those experiments were done in test tubes, not living cells. In the latest work, "we were delighted to find that the molecule showed robust activity in cells," said Mapp, an associate professor of chemistry. The artificial activator functioned even at low concentrations.
These results underscore the advantages of small molecules, which may be less likely to break down and easier to coax into cells than larger biomolecules, Mapp said.
The U-M researchers also found that their activator operates independently of the DNA-binding domain. "This tells us that the small molecule should be portable, and that we should be able to attach it to other DNA-binding domains and use it in different contexts," Mapp said.
Combined with earlier work, the latest results are further evidence that Mapp's molecules behave very much like natural activation domains, making them attractive candidates for eventual use in treating disease.
For Mapp's group, the next step toward that goal is attaching their artificial activation domains to different DNA-binding domains and assessing their function in animal cells. Once they're able to target specific genes, they plan to test their molecules in animal models of diseases such as medulloblastoma, a type of malignant brain tumor that mainly affects children.
"In medulloblastoma, genes that should be turned on, stay turned off," Mapp said. "It's been shown in animal models that if you can turn those genes back on, you selectively kill the cancer cells. The holy grail for us is to take a small-molecule based transcription factor and see if we can turn those genes on enough to induce the same function."
Mapp's coauthors on the JACS paper are graduate students Steven Rowe, Ryan Casey, Brian Brennan and Sara Buhrlage. Mapp received funding from the American Cancer Society, the National Science Foundation, the Alfred P. Sloan Foundation, Amgen and GSK. Buhrlage was supported by the U-M Chemistry Biology Interface Training Program.
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