Cells control mitosis (cell division) by assembling a biochemical switch to block it or by disassembling the switch to trigger it, according to investigators at St. Jude Children's Research Hospital and the Technical University of Munich.
The researchers found that when the switch called SCFNIPA is intact, levels of an enzyme called cyclin B1 drop, preventing the enzyme from activating a third protein called Cdk1. By blocking the interaction between cyclin B1 and Cdk1, SCFNIPA prevents the cell from dividing, the researchers said.
The finding helps explain how cells delay the onset of mitosis until the DNA in the nucleus has been properly duplicated and prepared for transport into the daughter cells that will arise when the cell divides. The current study shows that, in addition to a previously identified mechanism for controlling the level of cyclin B1 in the cell's nucleus, SCFNIPA also is key to controlling the level of that protein.
"If the cell starts to divide before the DNA has been properly duplicated and prepared for transport into daughter cells, the result could be two abnormal cells," said Stephan Morris, M.D., a member of the departments of Pathology and Hematology-Oncology at St. Jude. "Therefore, the role SCFNIPA plays in controlling the onset of mitosis until the cell can safely duplicate its DNA may mean the difference between healthy and unhealthy daughter cells--and perhaps even between normal cells and cancerous cells." Morris co-authored a report on this work, which appears in the July 15 issue of Cell.
The study found that NIPA (Nuclear Interaction Partner of ALK) is the timing device that determines when SCFNIPA triggers mitosis. When a molecule of phosphate (PO4-) is attached to NIPA, it cannot bind to SCF. The level of cyclin B1 rises during this time, which occurs when the cell is completing the duplication of its DNA (S phase), as well as during the subsequent preparatory phase and the early part of mitosis (G2 and M phases, respectively).
But when it sheds the attached phosphate molecule, NIPA binds to SCF to form SCFNIPA. The addition of NIPA makes SCF specifically target cyclin B1, sending that molecule to the proteasome, the cell's protein-degradation machine. This degradation of cyclin B1 occurs during the cell's resting phase, or interphase. In the absence of its partner cyclin B1 during interphase, the protein Cdk1 cannot trigger mitosis. While this process had been previously reported, the current study explains how it is regulated.
The investigators also showed that blocking the production of NIPA in a cell caused cyclin B1 to accumulate abnormally in the nucleus; this caused the cell to start dividing prematurely, before its duplicated DNA had been properly prepared for moving into new daughter cells.