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Study Throws New Light On How Gene Switches Operate

Faulty regulation of genes is a common basis of many human diseases, including many cancers.

Understanding gene regulation comes down to describing the components of gene switches and understanding how the various components work together to provide normal switch operation and, therefore, normal gene expression.

Now a discovery by Penn State College of Medicine researchers refutes an idea widely accepted by scientists and throws new light on how certain genes are regulated by gene switches.

This discovery reveals that a protein previously thought to be in the nucleus of the cell actually resides in the cytoplasm, the part of the cell that surrounds and interacts with the nucleus. Also, the study corrects a theory held since 1992 that describes the way the gene switch that regulates galactose metabolism operates.

These findings offer a new set of parameters for understanding gene switches as scientists search for the reasons why faulty gene switches cause illness.

The study, titled "Gene activation by interaction of an inhibitor with a cytoplasmic signaling protein," was published Monday in the online Proceedings of the National Academy of Sciences Early Edition and appeared in the June 25 print edition of the journal.

Gene switches determine how, when, and to what extent specific genes in the genome are turned on or off or modulated, said James Hopper, Ph.D., professor of biochemistry and molecular biology, Penn State College of Medicine, and principal investigator for the study. Understanding gene switches is germane to many diseases in humans. If the gene switch breaks down, all of the genes controlled by the switch show abnormal expression.

Abnormal expression may result when the gene's protein is not produced, too much of the protein is produced, or the protein is produced at inappropriate times under inappropriate conditions.

"We see one or the other of these circumstances in many human diseases," Hopper said. This is particularly true of cancer. It is now known that many cancers arise due to defects or faulty regulation of the very proteins that constitute gene switches.

The research in Hopper's lab is based on a model gene switch system in baker s yeast called the GAL gene switch. This switch controls the expression of genes that create the enzymes of the galactose pathway, a biochemical pathway that allows the body to turn galactose into energy. The galactose pathway, along with many of the basic cellular, molecular and biochemical processes that allow a cell to replicate and function are nearly identical in yeast and humans. This allows scientists to use yeast as a model research system for learning about normal human cellular processes and how defects in those processes bring about disease.

The yeast gene switch under investigation in Hopper's lab consists of three proteins, GAL4p, GAL80p and GAL3p.

We are looking at how these three proteins work to operate as the gene switch for turning on and off the galactose pathway genes and how defective galactose pathway genes give rise to galactose metabolism problems, Hopper said.

Previously, it was thought by scientists that GAL3p was found only in the nucleus of a cell. But, in fact, the work of a graduate student in Hopper' s lab, Gang Peng, shows that GAL3p is located in the cytoplasm. Gang Peng's research also shows that GAL80p is located in both the nucleus and the cytoplasm and can actually shuttle across between the two parts of the cell.

The gene switch is off when GAL80p is present in the nucleus and occupies the activation site of GAL4p. That prevents production of messenger RNA, and therefore prevents the copy of genetic information necessary to create the enzymes that break down galactose and create energy for the body.

The switch is turned on when galactose is introduced to the cell for processing. GAL3p latches on to GAL80p drawing it out of the nucleus and trapping it in the cytoplasm. This frees up the activation site of GAL4p and allows transcription factors to latch on. In this way, GAL4p proteins turn on the genes and create the enzymes that break down galactose.

Defects in the galactose pathway cause severe problems in both yeast and humans. Galactose is one of the substances produced when the body breaks down lactose, a sugar contained in dairy products. When cells can't properly process galactose, people develop galactosemia, a hereditary metabolic disease marked by the accumulation of galactose or its byproducts in the body. The build-up can lead to a number of symptoms and early death if not treated immediately by removal of galactose from the diet.

Since 1992, research relating to this gene switch was based on the idea that GAL3p goes in to the nucleus to latch on to a molecule of GAL80p that is tightly bound to a molecule of GAL4p.

In addition to correcting the scientific understanding of how this gene switch works, this research has uncovered a new way in which other gene switches might also work.

Hopper's laboratory team includes Gang Peng, Vepkhia Pilauri, Ph.D., Tamara Vyshkina, Ph.D., and Cuong Diep. Hopper's research on the GAL3p-GAL80p-GAL4p gene switch has been supported by the National Institutes of Health since 1976.

[Contact: Sean Young, Valerie Gliem]






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