Genes Play An Unexpected Role In Their Own Activation, Study Shows

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. CREB activates 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.

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 cAMP signals.

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."

"CREB is like a plumber who turns on the water flow in a pipe system by using a certain tool," Brindle said. "What we discovered is that the CREB 'plumber' requires different tools to turn on different genes; and that each gene determines which set of co-factor tools from CREB's toolbox it will respond to."

In order to activate a gene, CREB must first get "tagged" by a molecule called phosphate. CREB then recruits a co-factor called CBP/p300 to the gene by binding to this protein at a site called KIX. Previously, scientists thought that a particular transcription factor uses the same co-factors to activate all its target genes.

The new findings showed that phosphate-tagged CREB binding to CBP/p300 at KIX does not account for most gene activation controlled by the cAMP messenger molecule. Instead, the binding of CREB to KIX is necessary for only part of the activation of certain target genes; those genes became activated even when KIX was disabled in CBP/p300.

Further studies suggested that this KIX-independent mechanism can act on the same gene as the KIX-dependent mechanism; and that each mechanism may or may not contribute equally to activating a specific gene. The team also found evidence that other proteins can act as back-up co-factors for CBP/p300.

"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. "It is another clue to how CREB might activate the genes for enzymes that make glucose in the liver, while activating different genes in the brain that are key to learning and forming memories."

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 (St. Jude).

This work was supported in part by the National Institutes of Health, a Cancer Center (CORE) support grant and ALSAC.