Genes Play An Unexpected Role In Their Own Activation

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Investigators have discovered how a single molecular "on switch" triggers gene activity that might cause effects ranging from learning and memory capabilities to glucose production in the liver.

The "on switch," a protein called CREB, is a transcription factor -- a molecule that binds to a section of DNA near a gene and triggers that gene to make the specific protein for which it codes.

The St. Jude team showed that each gene that responds to CREB chooses which co-factors, or helper molecules, CREB uses to activate that gene. This finding adds an important piece to the puzzle of how cells use CREB to activate specific genes in response to a molecule called cAMP, which acts as a messenger for a variety of stimuli including hormones and nerve-signaling molecules called neurotransmitters.

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It also suggests that the current model scientists use to explain how CREB works is too simple, said Paul Brindle, Ph.D., associate member of the Department of Biochemistry at St. Jude. Brindle is senior author of a report on this work that appears in the June 20 issue of "The EMBO Journal."

"This more complex view of how CREB works may help us understand how this single transcription factor can stimulate many different genes, depending on which tissues are using it and which signaling molecule caused cAMP to put CREB to work," Brindle said.

A long-term implication of this work is that one day it might be possible to manipulate CREB's co-factors to treat disease. "A drug that blocked the specific co-factors CREB needs in the liver to trigger activity of genes that make glucose could reduce blood levels of this sugar in people with diabetes," Brindle said. "But at the same time, CREB could continue its other jobs without interruption."

Other authors of the study include Wu Xu, Lawryn Kasper, Stephanie Lerach and Trushar Jeevan.

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