by Brady Huggett

Yue Xiong's tool kit could help bring runaway cells to a screeching halt.

nderstanding cancer research at the cell level requires letting the mind drift inside a Lilliputian world that can’t be seen with the naked eye. Sometimes, it appears logical, simple, and efficient. Other times, surreal.

Why do cells lose the ability to sense when to stop growing and dividing? What makes cells grow until they have run amok, knotted into a tumor? Yue Xiong, associate professor of biochemistry and biophysics and member of the Lineberger Cancer Center, feels the answers may be encoded in the regulation of the cell cycle.

The cell cycle. Simple enough, really. A cell grows in size, gaining cytoplasm—the substance inside the walls of a cell—until it is ready to split. The chromosomes—bound-up DNA—are unwound and copied. At the point of cell division, one set of the chromosomes migrates to one side of the cell; the other set travels the opposite way. Then a cell wall is formed down the middle, and the cell halves itself.

Xiong uses a car analogy to help describe the proteins that drive this cell division process. The protein CDK is the engine of the process, and the protein cyclin is the gas. When these two combine, the engine runs and the cell divides. After the cell has divided, the cyclin, or the gas, is degraded, rendering CDK ineffective. The engine is still present and can be used when time for division again arises but for the moment has no fuel. Xiong was working with cyclin D, a form of cyclin that he discovered, when he found two proteins that have led his research in a new direction. He knew cyclin attached to CDK, but what he didn’t know was how it was able to do that. So he investigated, looking specifically for binding proteins. And while he was studying the engine and the gas, he found the brake of our cell car. These CDK inhibitors, as they are called, are named p21 and INK4 and bind to either the CDK-cyclin complex or to CDK alone, stopping cell growth and division.

“Without these two proteins,” Xiong says, “the engine would be running non-stop.”

And causing cancer.

“By finding these two inhibitor—or brake—proteins, p21 and INK4, we can understand how normal cells stop their growth when needed and why cancer cells don’t follow this rule,” Xiong says.

here are ways a cell recognizes mistakes in its DNA and stops growth. When an oncogene (cancer-causing gene) or damaged DNA is present, a protein named p53 arrives like a cop car called to the scene, Xiong says. It activates the p21 protein, which in turn applies the brake, stopping the cell cycle. This police protein is responsible for ceasing the spread of damaged DNA, for stopping the growth of imperfect cells.

P53 is a well-known tumor suppressor and the focus of much cancer research. Xiong and his colleagues, Wendell Yarbrough, a surgical oncologist, and Yanping Zhang, a postdoctoral fellow, have discovered that the ARF protein plays a significant part in p53’s job. When p53 is not needed, it’s led outside the cell’s nucleus and degraded as part of a normal, healthy cell cycle. However, when an oncogene is present, ARF awakens and prevents the exportation and degradation of p53. P53 then remains in the nucleus and activates p21 to stop the cell cycle. When things are functioning smoothly, ARF, p53, and p21 work competently and cell growth is correctly monitored. But, like a car, sometimes parts of a cell break down.

“In about 50 percent of tumors, p53 is mutated and can no longer activate p21,” Xiong says. “In about 40 percent of tumors, the ARF protein is mutated and can no longer stop p53 from being exported. The combined mutation of p53 and ARF, as you can see, is very high. We believe either one, ARF or p53, is mutated in nearly all tumor cells.”

Next: "multiple targets to aim at"
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