Steve Hann works under the tissue culture hood in his lab. Hann discovered a smaller version of a protein that may have implications in cancer research. (photo by Dana Johnson)
Oncogene research provides piece of puzzle
Vanderbilt University Medical Center researchers have put another piece in the puzzle of how a gene that is involved in many different types of cancer works. The gene, c-myc (pronounced ‘mick’), is critical for normal cell division and cell death. Understanding exactly how it participates in these processes could lead to strategies for manipulating its actions to cause tumor cells to die.
Myc is one of the original “oncogenes,” first discovered as part of a tumor-causing virus. It was then also found in regular cells, where it participates in normal cell division (cell growth) as well as in processes that instruct cells to die.
The Myc protein is a “transcription factor”—it controls the expression of other genes, turning some on and others off. Scientists believed that Myc worked mainly by turning genes on, particularly genes that are important for cell growth.
But two years ago, Stephen R. Hann, Ph.D., professor of Cell Biology, and colleagues discovered a smaller version of the Myc protein that can not turn other genes on. This short Myc, made from the same gene as the regular Myc protein, can still shut down gene expression. And the short Myc can still stimulate cell division, transform normal cells into cancer cells, and cause cells to die—all the things the regular Myc protein can do.
“Our results destroyed the whole model of how Myc works,” Hann said. “They suggested that transactivation (turning genes on) cannot really be the main function of Myc.”
So Hann and colleagues began to explore the genes that Myc represses, or turns off. In the current studies, reported in the Proceedings of the National Academy of Sciences, they show that Myc represses expression of a gene called p21CIP1—an inhibitor of cell growth.
Previous research conducted by Dr. Harold L. Moses, director of the Vanderbilt-Ingram Cancer Center, and others had tied both Myc and p21 to the actions of transforming growth factor beta (TGFbeta), a powerful growth suppressor. TGFbeta, acting through receptor signaling pathways, reduces the amount of Myc and increases the amount of p21 in cells.
Hann and graduate student Gisela F. Claassen showed that these actions are related: in cells that have been exposed to TGFbeta, first Myc goes down and then p21 goes up. When they experimentally elevated the amount of Myc in the cell, TGFbeta could no longer work to increase p21.
“Myc can totally wipe out the ability of TGFbeta to turn on p21,” Hann said. “This could be how Myc overcomes the ability of TGFbeta to inhibit cell growth.”
The findings have implications for understanding what happens when Myc function is perturbed in tumors. In the future, it may be possible to alter Myc activity to halt tumor growth, or even to kill tumor cells.
Hann suggests that Myc does most of its work by repressing genes. In his model, Myc promotes cell death by turning off cell survival genes, and it launches the uncontrolled cell growth that occurs in tumors by turning off growth inhibitors like p21.
“We need to figure out what the important Myc target genes are,” Hann said. “When we do, we may be able to tinker with the system so that in tumors where Myc is involved, we can push the cells towards cell death and kill them off.”
Finding the critical target genes will not be easy, Hann said.
“Myc is probably one of the most studied oncogenes, and at the molecular level, it’s still a big question mark.”
The work was supported by the National Cancer Institute.