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UNC studies target molecular defects implicated in cancer, genetic diseases

CHAPEL HILL -- In three separate studies, scientists at the University of North Carolina at Chapel Hill School of Medicine have shown that it is possible to correct defective molecular splicing pathways that would otherwise contribute to cancer, genetic diseases and possibly other disorders.

These corrections were accomplished by the insertion into the cell of antisense oligonucleotides, short strands of genetic material that target portions of RNA. RNA carries the DNA blueprint for cellular protein production in gene expression. The technique for correcting these defective molecular splicing pathways was pioneered by Dr. Ryszard Kole, professor of pharmacology and a member of the UNC Lineberger Comprehensive Cancer Center.

In a new study published Dec. 20 in the Journal of Biological Chemistry, Kole and colleagues used these techniques to eradicate certain cancer cells or to increase their sensitivity to treatment.

While tumors initially respond to radiation or chemotherapy, they frequently become resistant to subsequent treatments. One form of resistance develops when cancer cells no longer respond to signaling molecules that tell the cells to die, a process known as apoptosis. In the new report, RNA splicing of the gene that controls apoptosis was targeted with antisense oligonucleotides.

"RNA splicing is the essential process of cutting and pasting the genetic code into a continuous reading frame to produce protein," said Kole. "The cell can splice each RNA into multiple, alternative forms, which result in related but different proteins. In cancer cells, this process may be modified and contribute to resistance to apoptosis."

For example, RNA coded by a gene, bcl-x, is alternately spliced into two different forms, both of which play an important role in apoptosis. The short form, bcl-xS, promotes apoptosis and cell death, while the long form, bcl-xL, prevents apoptosis and promotes cell growth.

Accordingly, higher levels of bcl-xL
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Contact: Leslie Lang
LLANG@MED.UNC.EDU
919-843-9687
University of North Carolina School of Medicine
8-Jan-2003


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