Brave New World of Small Transcription Activators

In the quest for new approaches to treating and preventing disease, one appealing route involves turning genes on or off at will, directly intervening in ailments such as cancer and diabetes, which result when genes fail to turn on and off as they should.

Scientists at the University of Michigan and the University of California at Berkeley have taken a step forward on that route by developing small molecules that mimic the behavior and function of a much larger and more complicated natural regulator of gene expression. The research, by associate professor of chemistry Anna Mapp and coworkers, is described in the current issue of the journal ACS Chemical Biology. _GenengNews

Throughout the lifespan of an organism, various genes are continuously being turned on and off, depending upon the needs of the cells, tissues, and organism. Disease and ageing can interfere with the normal process of gene activation and de-activation, as well as other aspects of normal gene expression. U Michigan and UC Berkeley researchers are discovering relatively simple molecules that might be used to artificially restore normal gene function in the ageing and / or diseased orgamism.

In the current work, the team showed that their ATFs bind to a protein called CBP, which interacts with many natural activators, and that the specific site where their ATFs bind is the same site utilized by the natural activators, even though the natural activators are much larger and more complex.

Then the researchers altered their ATFs in various ways and looked to see how those changes affected both binding and ability to function as transcriptional activators. Any change that prevented an ATF from binding to CBP also prevented it from doing its job. This suggests that, for ATFs as for natural activators, interaction with CBP is key to transcriptional activity.

"Taken together, the evidence suggests that the small molecules we have developed mimic both the function and the mechanism of their natural counterparts," said Mapp, who has a joint appointment in the College of Pharmacy's Department of Medicinal Chemistry. Next the researchers want to understand in more detail exactly how the small molecules bind to that site. "Then we'll use that information to design better molecules." _GenengNews

The gene expression process has many entry points. In order to tame the natural processes of disease and ageing, scientists will have to master most all of them. Like most important areas of scientific progress, these discoveries contain both promise and hazard.