$1.1 Million Grant To Study Factors Controlling Cell Division
St. Louis, May 19, 1999 Helen Piwnica-Worms, Ph.D., professor of cell biology and physiology at Washington University School of Medicine in St. Louis, has received a four-year $1.1 million grant from the National Institute of General Medical Sciences. Piwnica-Worms will analyze the molecular factors that regulate a cell's decision to divide into two daughter cells. When regulation goes astray, cells divide unrestrainedly into tumors.
In some ways, a cell resembles a new-fangled car that won't move until the driver is buckled in.
A cell divides only if molecular sensors detect that its genetic material, DNA, is ready. Having undamaged DNA is crucial prior to division because DNA provides the molecular blueprint daughter cells need to survive.
Piwnica-Worms will clarify how the two major DNA sensors help cells make the division decision. These sensors, which are similar in yeast cells and human cells, check for damage to DNA and check whether the DNA has been faithfully duplicated.
Piwnica-Worms will study how two factors regulate a component of the DNA damage sensor, a protein called cell division cycle molecule 25C (Cdc25C). When DNA is in good shape, Cdc25C activates another protein that switches on cell division.
Her laboratory previously helped identify proteins called Chk1 and Cds1 in human and yeast cells that prevent Cdc25C from activating the switch if a cell's DNA is damaged or not faithfully replicated. Piwnica-Worms will study how Chk1 and Cds1 interact with Cdc25C.
The molecular switch, Cdc2, also is regulated by other proteins. Piwnica-Worms will determine whether a regulator called Wee1 in human and yeast cells keeps the switch from working when division is inappropriate.
The Wee1 protein is found in the nucleus, where sensors are thought to evaluate DNA's readiness for cell division. But a regulator found outside the nucleus in cells of humans and other many-celled organisms might inhibit Cdc2 activity early on. Piwnica-Worms hopes to discover which regulator plays this role and whether the regulators act on other proteins.
She also will study mutated forms of the second regulator to determine how it interacts with targets. This work could reveal a way to keep Cdc2 outside the nucleus, preventing it from triggering cell division.
"If you could keep Cdc2 out of the nucleus," Piwnica-Worms says, "cells such as cancer cells would never divide."
The research also might suggest other ways to kill cancer cells. For example, it might suggest ways to disable the DNA damage sensor to make cancer cells divide when they cant survive. Piwnica-Worms notes that a drug that acts in this way is currently in early clinical trials.
In other work, she also will study interactions between the sensor components that evaluate DNA duplication and those that detect DNA damage. Piwnica-Worms already helped identify an inhibitor of Cdc25C that is important at both checkpoints.
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