Sampling real breast cancer cells from a tumor bank, Reed's team found that cells with high levels of cyclin E also tended to have high levels of Cks. Since neither protein directly influences the level of the other, the implication was that an initial oncogenic overactivation of cyclin E must in most cases be followed by Cks overexpression to keep a cell on the path to full-blown cancerous growth. "The statistical link between the cyclin-E and Cks levels was so strong that it could not have been a coincidence," said Reed.

Cks's cancer-enabling potential appears to be a broad one. When Reed's team looked at incipient cancer cells whose growth was driven by a different oncogene, h-Ras, they again found that the oncogene provoked checkpoint-dependent slower growth, whereas Cks overexpression partially nullified it and allowed cell division to proceed almost as normal.

Looking Ahead

In recent years, other researchers have noted that an initial oncogene activation can trigger a slightly different kind of growth arrest in cells. The phenomenon, known as oncogene-induced cellular senescence, is believed to underlie the slow or stopped growth of skin moles and some benign cancers. "It has been shown that this induced senescent state depends in part on the persistent activation of cell-cycle checkpoints, so presumably it is related to the process affected by Cks," said Reed.

Reed and his team are now trying to determine the precise molecular events through which Cks proteins exert their checkpoint-nullifying effect in cancer. At the same time, they are looking for ways to use their new knowledge against Cks-overexpressing cancers. The most direct strategy would be to treat cancer, or prevent it in people with inherited predispositions, simply by using a drug to reduce the activity of Cks proteins.

"We know that we can delete half of the Cks genes from mice without any deleterious effects, and this reduces the frequency of tumor formation," said Reed. "So the chances are we could find a way to reduce Cks proteins' activity enough to prevent their checkpoint-override effect while still allowing their essential cell functions."

Source: Scripps Research Institute