Photo by Todd McNaught
Center researchers have discovered a link between two well-known cancer proteins that sheds new light on why each contributes to so many types of tumors.
The study, led by postdoctoral fellows Drs. Amir Orian (Oryan) and Markus Welcker, focused on a protein known as Myc, which is essential for cells to grow when present in modest amounts. Scientists have long known that Myc can become a key driver of many types of cancers when cells contain too much of it.
The new study reveals that another protein, Fbw7, controls Myc levels and earmarks Myc for destruction when it is no longer useful. This finding implies that cells lacking Fbw7 will accumulate abnormally high levels of Myc and provides new insight into why Fbw7 is frequently absent or altered in many different types of cancer. In addition, the study helps to explain the significance of a particular Myc defect commonly found in cells of patients with a particular form of lymphoma. In this case, the defective part of Myc causes the protein to evade recognition by Fbw7.
The researchers speculate that the findings could open the door to the development of new cancer therapies that work by restoring Fbw7 function to cells that lack it.
The study also resolves a long-standing puzzle about how cells control Myc levels, said Dr. Bob Eisenman, whose Basic Sciences Division laboratory led the study along with that of Dr. Bruce Clurman of the Clinical and Human Biology Divisions.
"For many years, we've known that the amount of Myc in the cell really matters in terms of whether cancer develops," said Eisenman, who has studied the protein for more than 20 years. "We also have known that Myc levels are tightly controlled because the protein is rapidly turned over — that is, it's degraded soon after it is made. These new findings explain how that turnover is controlled."
Other systems in the cell cause Myc degradation, but only Fbw7 earmarks Myc for destruction in response to environmental cues that tell the cell that growth should cease — which helps explain Fbw7's link to cancer. What's more, Welcker and others have previously shown that Fbw7 controls the destruction of several other proteins that help keep cell division at a healthy pace.
"Our new findings tie together the turnover of proteins involved in both cell growth and cell division, " said Welcker, a postdoc in the Clurman lab. "Excess amounts of any of these proteins can lead to cancer."
Before a cell divides, it must grow in size — a process in which Myc plays a key role. Cells also must manufacture a collection of cell-cycle proteins that carry out key steps in the division process. As the cell-cycle proteins accumulate in succession, the cell is pushed through a series of steps that allow a single cell to duplicate its chromosomes, pull them apart and segregate them into two new daughter cells.
"The timing for destruction of all of these proteins is very important," Welcker said. "Timely destruction ensures that the cell cycle only goes in one direction — and that cells don't divide more rapidly than they should. The proteins need an earmark for destruction, which is the role played by Fbw7 and other proteins like it. This earmark itself is very short-lived, so it took decades before this was clearly understood."
The collaborative study between the Clurman and Eisenman labs revealing Fbw7's importance in this process emerged when independent lines of investigation in each lab converged.
Orian's studies of Myc, which he conducts through genetic analysis of the fruit fly Drosophila, had focused on the protein's ability to switch on dozens of genes important for cell growth.
"We have found that Myc binds to about 15 percent of genes presumed to be active in the genome, and there are so many target genes regulated by Myc," he said. "It became obvious that the best way to learn more about it was to understand how Myc itself is regulated, and to identify factors common among many organisms that negatively regulate Myc, such as Fbw7."
At the same time, Welcker had focused on identifying proteins earmarked by Fbw7 for destruction. Last year, he discovered that one of Fbw7's targets was a protein called cyclin E, which controls cell division. He and Orian recognized that cyclin E and Myc both possess a common feature that allows it to be tagged for demolition by Fbw7. The ensuing collaboration revealed that indeed, both Myc and cyclin E are subject to the same destruction pathway.
Clurman said the findings have broad implications for the understanding of how tumors develop.
"The results provide insight into both how loss of Fbw7 affects cancer development and how Myc is regulated in both normal and cancer cells," he said. "In addition, this work helps us to further understand the proteins earmarked by Fbw7, which may reveal therapeutic targets for tumors that have Fbw7 mutations."