What ensures that Cdc2 is irreversibly turned ON or OFF at mitotic entry and exit, respectively? Does the switch function like a buzzer or a toggle?
"A buzzer is ON when one pushes hard enough on its button and stops buzzing when one lets go. A toggle likewise switches on when one pushes hard enough on the lever in one direction, but it will stay on when one lets go," says Tyson. "To switch a toggle off, one must push the lever with sufficient force in the opposite direction. Engineers call this sort of behavior hysteresis."
By manipulating the concentration of cyclin in cytoplasmic extracts prepared from frog eggs, the Virginia Tech investigators pushed the "button" for Cdc2 to see how the switch responded. To turn Cdc2 ON and trigger entry into mitosis required a push of at least 40 units of cyclin. When they let up on the pressure (by letting cyclin concentration drop to 30 or even 20 units of cyclin), the switch stayed ON, that is, Cdc2 remained active and mitosis persisted. To turn the switch OFF (inactivate Cdc2 and exit mitosis), required cyclin levels to drop to 16 units or less. These experiments demonstrated that the control system is bi-stable and hysteretic.
What regulates these irreversible switches has been a big question, Sible explains. "Others have published mathematical models of the cell cycle that function without hysteresis. It was not until we put our model to the test that we could determine that hysteresis is the basis of the switches that start and stop mitosis."
These experiments were performed in cell-free extracts derived from frog eggs. The frog egg extract system is the most simple eukaryotic cell cycle system but is representative of cell cycles in other organisms including humans. "We know from many years of research, including that resulting in the 2001 Nobel Prize in Physiology or Medicine, (awarded
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Contact: Jill Sible
siblej@vt.edu
540-231-1842
Virginia Tech
30-Dec-2002