One of the highest-scoring abnormalities -- meaning it had a high potential to cause rampant cell growth -- involved a gene known as p18INK4C. Researchers knew that one of p18INK4Cs cousins, a tumor-restraining or suppressing gene called p16INK4A, is missing in a majority of glioblastoma cases. p18INK4C itself, however, wasnt previously known to be missing in the disease. Although the two genes are thought to have similar functions, investigators suspected the co-disappearance was more than a coincidence, and that the loss of p18INK4C plays a role in glioblastoma.
Based on the algorithmic analysis, lead author Ruprecht Wiedemeyer, PhD, a postdoctoral fellow in Chins lab, went in search of a connection between p16INK4A and p18INK4C that can explain their joint disappearance. It turns out that the loss of p16INK4A triggers a shutdown of a pathway (a series of interconnected genes) called RB. That, in turn, causes cell proliferation and a giant step toward cancer. At that point, p18INK4C steps in as a backup system, pulling the reins on the hectic cell growth permitted by the loss of p16INK4A. If p18INK4C is lost, its as though the emergency brake on growth is gone.
We found that p16 and p18 are part of a feedback loop that keeps the growth of normal glial cells in check, Chin states. When p16 goes out of commission, p18 is signaled to pick up the slack. We demonstrated that the deletion of both genes is required for glioblastoma to develop.
The feedback loop is the latest evidence that cancer gene pathways are not as straightforward as scientists once thought them to be. Just a few years ago, the view was that pathways were largely linear, Chin comments. Were in
|Contact: Bill Schaller|
Dana-Farber Cancer Institute