New Discovery May Lead To Control of Production of Key Proteins

April 15, 1999

Scientists are closing in on discovering the way that the body regulates critical proteins involved in the front line defense against disease as well as in normal body processes.

The discoveries could lead to development of pharmaceuticals to control the body''s production of these proteins.

An article in the April 16 issue of Science, for the first time links the destruction of proteins to the destruction of the molecules that create those proteins, called messenger RNA. Gary Brewer, Ph.D., associate professor of microbiology and immunology at Wake Forest University Baptist Medical Center, is a co-author,

Brewer said the messenger RNAs under study encode many proteins of high interest in medicine: cytokines, which are important for immune response -- the defense against disease-- and cell development; oncoproteins, important for both normal cell growth and in the uncontrolled cell growth of cancer; and proteins that directly affect heart function.

The new results build upon previous discoveries by Brewer and his colleagues, dating back to 1986. One key discovery, in 1991, was of a protein that they called AUF1, which binds to the messenger RNA.

"It has been known for some number of years that there are enzymes that are involved in the degradation process of proteins, just as there are enzymes that are involved in the degradation process for messenger RNA," Brewer said.

One enzyme involved in the destruction of proteins is called the proteasome. "One of the implications of this work in terms of mechanism is that this protein, AUF1, binds to the RNA targeting sequences, which makes the messenger RNA unstable," Brewer said.

"How does the degradation of messenger RNA occur? What this paper would seem to indicate is that the proteasome''s destruction of AUF1 somehow permits the degradation of the messenger RNA to which AUF1 is binding."

This discovery could lead to ways to control the production of cytokines, oncoproteins and the proteins involved in heart function.

"From a pharmaceutical point of view, it would be advantageous to be able to control the expression of these gene products," Brewer said. "One means to control the expression of these proteins would be to control AUF1 because it determines how much of these messenger RNAs are going to be present in the cells," he said,

For example, he envisioned a drug that enhanced the binding of AUF1 to its RNA target. "If the drug enhanced the binding of this protein, you might predict that you might get less of the cytokine or oncoprotein. If you had a compound that blocked the binding of AUF1 to its RNA target, then you might be synthesizing more of the cytokine or oncoprotein."

Brewer stressed that even the ominous sounding oncoproteins are essential to normal cellular processes.

"There might be situations where it would be advantageous to turn them off. There would be other situations where you might want to turn them on. It may be possible not to just turn them on or off, but modulate expression of cytokines and oncoproteins by controlling the ability of AUF1 to bind to the RNA target."


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