St. Jude 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.
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, PhD, Biochemistry. 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.