Thursday, July 12, 2007

Gene activation by CREB

Here's more illustration, if any were needed, of the point that gene expression is a much more complex process than has sometimes been supposed. We recall that transcription factors are proteins that are necessary for a gene to be expressed, and they do their job by binding to a section of DNA (called a promoter) near the gene. To make matters more interesting, it is usually necessary to have other proteins involved, and some bind to the transcription factor rather to the promoter. Such proteins are called cofactors. If the effect is to increase gene expression, the protein is called a coactivator. You may recall that a coactivator played an important role in this post about metering gene expression.

As it happens, we mentioned an important type of transcription factor, called cAMP responsive element binding proteins (CREB) in our recent post on histone deacetylase enzymes. The general situation is that a CREB is part of a cell-signaling pathway, in which a signal arrives at a cell surface, activating some cell surface receptor. As a result, a secondary signal is generated within the cell, consisting of a cAMP molecule, which in turn activates a protein kinase, which finally activates a CREB protein. This last may then act as a transcription factor, causing a particular gene to be expressed, with the resulting protein being the cell's response to receipt of the original signal.

The interesting thing is that, according to the following research, the target gene "chooses" which cofactors are needed along with the CREB to initiate gene transcription. (Is that really surprising? I don't know. It seems one might have guessed that each gene promoter requires something slightly different to allow transcription, so that transcription depends not only on the received signal, but also on other varying conditions.)

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

Investigators at St. Jude Children's Research Hospital 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.

One of the report authors, Paul Brindle, offers this analogy:
"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."


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