DURHAM, N.C.—Researchers at the Duke Institute for Genome Sciences and Policy have gained insight into the hidden properties of an "on-off" switch that governs cell growth, a discovery that may provide clues to novel drug targets for cancer and other diseases in which cell growth goes awry.
In a study published in the April issue of Nature Cell Biology, Duke team concluded that if the switch is on, a cell will divide, even if it is damaged or the signal to grow disappears.
Led by Guang Yao, a postdoctoral fellow in Duke's department of molecular genetics and microbiology, the research team included Tae Jun Lee, Seiichi Mori, Joseph R. Nevins and Lingchong You. The study was funded by the National Institutes of Health the National Science Foundation and a David and Lucile Packard Fellowship.
The switch—part of the Rb-E2F—is part of a critical pathway that controls cell division. Before a cell starts to divide, it goes through a checklist to make sure everything is in order. If a cell senses something is wrong early on, it can halt the process. But once a cell passes a milestone called the restriction point (R-point), cell division cannot be stopped. The switch controls this milestone and is key to cell growth.
"The R-point marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation," the researchers wrote. "It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers."
During the project, Yao discovered the switch might represent a bistable condition, maintaining its "on" state once it is turned on by an external signal, even if the signal disappears. The research team then broke down the pathway into individual chemical reactions that could be described by mathematical equations, verifying the results in laboratory experiments on single cells.
"Using single-cell measurements, we show here that the Rb–E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses," the researchers wrote. "Once turned on by sufficient serum stimulation, E2F can memorize and maintain this on state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point."
Nevins, who has studied the Rb-E2F pathway for 20 years, sees an opportunity to extend this approach to other critical aspects of cell behavior, such as the decisions involved in cell death.
"This pathway, and this decision whether it is time to proliferate, is very tightly coupled to decisions of cell fate," Nevins said. "There's a decision as to whether the proliferation process is normal, and if answer is not, then the result is that the cell dies. We don't know critical dynamics of that process."