July 18, 2005
Alternating Rise and Fall of SCF – NIPA Levels Act as Switch Regulating Cell Division
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.
"It's tempting to speculate that inactivation of NIPA can destabilize genes, which is something that is frequently observed in cancer cells," said Justus Duyster, M.D., professor of medicine in the Department of Internal Medicine, at the Technical University of Munich, Germany. "Therefore our future work with St. Jude will include studying the activation state of NIPA in various tumor tissues, among other investigations." Duyster is senior author of the Cell paper.
SCFNIPA is one of a family of enzymes called E3 ubiquitin ligases. These enzymes regulate the levels of certain proteins that would otherwise wreak biochemical havoc if they were always present and active, Morris said. Specifically, these enzymes tag proteins with a molecule called ubiquitin, a process called ubiquination. When a protein is ubiquinated, the tag alerts the cell to send the protein to the proteasome for destruction.
NIPA is a so-called F-box-containing protein. F-box-containing proteins recruit specific target molecules to E3 ubiquitin ligases so that they can be tagged for destruction. In the case of SCFNIPA, the molecule recruited and tagged for destruction is cyclin B1. The laboratories of Duyster and Morris had previously showed that NIPA interacts in cells with ALK (Anaplastic Lymphoma Kinase), a protein that can cause certain human cancers when mutated. ALK was discovered in the early 1990s by Morris and his colleagues at St. Jude.
Other authors of the paper include Florian Bassermann, Christine von Klitzing, Silvia Mnch, Ren-Yuan Bai and Christian Peschel (Technical University of Munich) and Hiroyuki Kawaguchi (St. Jude).
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