Hagedorn focuses on RNA regulation to fight cancer

Cells tightly regulate the activity, or expression, of genes to achieve the fine-tuned balance required for the health of the whole organism. Cancers, often associated with aberrant expression of genes that govern basic cell processes such as growth and division, upset this balance. In cancers, these genes, called cell cycle regulators, are over-expressed, resulting in rapidly dividing and growing cells. Curt Hagedorn, associate professor of medicine, is interested in targeting this deregulation of genes as a means to fight certain cancers. To accomplish that, Hagedorn is not focusing on the genes themselves, but rather the messages these genes encode.

DNA, which contains the genetic information used by most organisms, resides in the cell's nucleus, from where it directs all the activities of the cell. The genetic information along the DNA strand is transcribed by special proteins into a message molecule known as messenger RNA (mRNA). This mRNA is then processed and transported outside the nucleus into the cytoplasm of the cell where proteins will be synthesized (translated) based on the mRNA molecule's message.

The cell must protect this mRNA message to prevent it from being degraded by enzymes before the protein it encodes is fully made. One way that cells protect their mRNA is by putting a chemical structure called a "cap" at the beginning of the mRNA. This cap can be compared to the plastic covers on the end of a shoestring. The chemical cap protects the mRNA, while it also acts as a structural beacon that binds other molecules. For example, it aids in transport of the mRNA out of the pores of the nucleus and helps to recruit the machinery responsible for translating the mRNA message into protein. This last function is necessary for the construction of the protein originally encoded by the gene (DNA) in the nucleus.

In his research on breast cancer supported by a National Institutes of Health Shannon Award, Hagedorn is attempting to disrupt the protein synthesis of abberrantly expressed genes in tissue culture cells derived from breast cancers. He and his colleagues plan to design pieces of RNA (antisense RNAs) that will stick to the end of the mRNA message of interest and prevent the protein synthesis machinery of the cell from recognizing it. Already the researchers have demonstrated that they can affect the ability of certain elements to bind to the mRNA cap. Their research has shown that some of their "sticky" RNA molecules can disrupt binding of protein synthesis machinery to the mRNA, and surprisingly some of the other RNA molecules they designed actually enhance the interactions. If the protein that is originally encoded by the over-expressed or misregulated gene cannot be translated from that gene's mRNA message, over-expression of the gene should not have deleterious effects on the cell's growth and division.

Hagedorn also is investigating the biology of Hepatitis C virus in his lab. A major liver disease, Hepatitis C infects nearly 3.5 million people in the United States. The virus has all of its genetic information encoded by RNA, and special proteins are needed to transcribe the genetic information of the RNA genome of the virus into mRNA messages recognized by the protein synthesis machinery of the infected cell. To do this the virus uses an enzyme called an RNA dependent RNA polymerase. Hagedorn capitalizes on his knowledge of RNA regulation to study this unique enzyme required by Hepatitis C in the hope that this enzyme will eventually provide a good therapeutic target for Hepatitis C treatments.

Hagedorn's Shannon Award to study the disruption of cell cycle genes in breast cancer has recently been resubmitted and awarded a full four-year grant from the National Institutes of Health.

--Michele Arduengo