Turning Genes Up, Not On: A New View of the Myc Protein
One of the best studied proteins in cancer research is also one of the most mysterious.
Myc helps control genes involved in cell growth and is associated with many cancers. But, after thousands of studies, researchers still do not know important details about how Myc operates in normal cells and in cancer cells.
Two new studies, however, cast this large body of work in a new light, providing some answers and raising new questions. Myc, the studies found, apparently boosts the expression of nearly all active genes in a cell, rather than activating specific genes.
"Whatever a cell is doing, it will do that more intensely under the influence of Myc," said Dr. David Levens of NCI's Center for Cancer Research, who co-led one study with Dr. Keji Zhao of the National Heart, Lung, and Blood Institute. Both studies appeared in Cell last week.
A New Perspective
Dr. Levens and his colleagues tracked the activity of Myc in white blood cells using molecular "tags." This approach revealed that Myc does not preferentially interact with any specific gene; instead, the protein is present at nearly every gene that is already expressed.
Using different methods and types of cells, Dr. Richard Young of the Whitehead Institute for Biomedical Research and his colleagues reached a similar conclusion in a second study. "We came to realize that the primary role of Myc is to go to all the genes that are active in a cell and act like a rheostat, turning up their expression," said Dr. Young.
These are very well done studies, noted Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania and a Myc researcher who was not involved in the work. "They provide an additional view of how a relatively powerful cancer gene works when it is deregulated."
We came to realize that the primary role of Myc is to go to all the genes that are active in a cell and act like a rheostat, turning up their expression.
—Dr. Richard Young
But the model, he added, does not account for some well-documented observations about Myc.
"We know, for instance, that Myc inhibits the differentiation of cells," Dr. Dang said. "So that means that instead of only amplifying the expression of active genes, the protein has to inhibit something in cells. These studies acknowledge that not all active genes are turned up; in fact, up to one-third are repressed."
Another important question, Dr. Dang noted, is how high levels of Myc might contribute to cancer. "If you crank up Myc to very high levels and it still behaves as an amplifier, does that cause the expression of genes to occur in an imbalanced way and alter [RNA in a way] that could lead to cancer?" he asked.
These and similar questions could keep researchers busy for a long time, noted the authors of an accompanying editorial. These "seminal" studies provide a first "glimpse of a coherent and holistic view of Myc," wrote Dr. Gerard Evan and two colleagues at the University of Cambridge in the United Kingdom in the editorial.
This view of Myc suggests there will never be a single transcriptional signature—a set of genes consistently activated by the protein. This is because the activity of Myc depends entirely on the type of cell and which state the cell is in when Myc is activated, according to the new model.
Implications for the Future
If the new results are confirmed, they could have implications for cancer researchers. Drug developers might want to disrupt the cellular machinery involved in the amplification effect of Myc rather than focusing on specific genes, noted Dr. Young.
"If Myc is amplifying all of the active genes in a cell, the idea of targeting just some of those genes appears unlikely to succeed," he said. "Going after Myc may be more fruitful." He predicted that the new results could "reinvigorate efforts to drug Myc itself," though Myc, like other transcription factors, has proven to be an elusive target.
Researchers have been looking for a pathway through which Myc operates for many years. "Our results suggest that Myc will cooperate with any oncogenic process," said Dr. Levens.
Before launching this study, Dr. Levens wondered whether he could add anything new to the large scientific literature on Myc. He now sees the new model as bringing together and explaining many puzzling and often contradictory observations about the biology of Myc.
"Our study is more integrative than it is novel," he said. "It's hard to say something really new about this protein."
—Edward R. Winstead