Wednesday, July 04, 2007

Metering gene expression

As often noted, such as here, gene expression is really quite a complicated process.

Although the net result of DNA transcription is the production of messenger RNA under control of a complex enzyme called RNA polymerase, there's a lot more to it than that. In particular, transcription will usually not even begin unless certain proteins, called transcription factors, have attached themselves to a location on the DNA specific to each gene (called a promoter region). Such proteins are called activators because of the role they play.

To make matters even more complicated, sometimes additional proteins, called coactivators, must be attached to other activators instead of the DNA itself. Since transcription factor proteins are produced under control of other genes, this complex process makes it possible for certain genes to control or regulate the expression of other genes. Indeed, this is the normal state of affairs, and it works much like a computer program, in which the "final" result depends heavily on what else is going on at the same time or earlier.

It now appears that there is a further complication, and hence a further sort of control that is possible. In general it is not desirable that any particular gene remain "on" indefinitely, capable of directing the production of its corresponding protein without limits. Just as with a prescription medicine (which, in some sense, many of the proteins encoded by genes really are), it is often best to dispense only a certain limited quantity. This quantity may be sufficient for whatever its purpose is, and the system may need time to absorb it, with the possibility of producing more later if, and only if, the need still exists.

Research now indicates that in order to allow for such metered usage, some coactivators make it possible to keep a count of how often they are used, and they will automatically be destroyed after the maximum allowed number of uses is reached.

Clocking In And Out Of Gene Expression
"Inherent to the structure of these coactivators is a clock," he said. "But the clock needs to be set off." In studies of breast cancer cells, [senior investigator Dr. Bert] O'Malley and his colleagues showed how the clock works. Using steroid receptor coactivator-3 (SRC-3), they demonstrated that activation requires addition of a phosphate molecule to the protein at one spot and addition of an ubiquitin molecule at another point. Each time the message of the gene is transcribed into a protein, another ubiquitin molecule is chained on. Five ubiquitins in the chain and the protein is automatically destroyed.

"It's built-in self destruction," said O'Malley. "It prevents you from activating a potent factor in the cells that just keeps the clock running and the gene continuing to be expressed." In that scenario, the result could be cancer, too much growth or an abnormal function.

"It means there's a fixed length of time that the molecule can work. When it's activated, it's already preprogrammed to be destroyed. The clock's running and each time an ubiquitin is added, it is another tick of the clock." When the clock system fails, problems result.


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