Scientist Identify Proteins That Regulate Cell Divison

August 28, 1997

St. Louis, Aug. 27, 1997 -- Researchers have discovered how key molecules interact in the major pathway regulating cell division. When disrupted, this pathway can cause cells to divide prematurely, a finding that the scientists suggest may lead to novel approaches to chemotherapy. The researchers report their findings in two papers in the Sept. 5 issue of Science.

''If you disrupt this [regulatory] pathway, cells can't stop dividing even though their DNA is damaged,'' says Helen Piwnica-Worms, Ph.D., lead author of the first paper. ''So deliberately disrupting this pathway may force cancer cells to divide before they are ready. Their daughter cells would then die,'' she says.

Piwnica-Worms is an associate investigator of the Howard Hughes Medical Institute and an associate professor of cell biology at Washington University School of Medicine in St. Louis. Her research was supported by funding from the Howard Hughes Medical Institute and from the National Institutes of Health.

Her research developed from the study of a molecule that promotes cell division, called cell division molecule 25C, or Cdc25C. Previous work had revealed that Cdc25C activates another protein called Cdc2, the molecular switch that turns on cell division. In this first study, Piwnica-Worms looked further back in the regulatory pathway to see how Cdc25C is controlled.

Using genetically altered cells that expressed Cdc25C or a mutant form of the protein, Piwnica-Worms showed that the normal protein loses a phosphate group at a potentially important site right before chromosome duplication and segregation, the mitosis that occurs as a cell begins to divide. The mutant molecule could not receive a phosphate group at this site, Piwnica-Worms found. Cells that made this abnormal protein also had fragmented chromosomes, suggesting they had entered mitosis before their genetic material could be safely duplicated. So the absence of the critical phosphate group on Cdc25C allowed cells to divide prematurely, it seemed.

Cdc25C appears to be a target of pathways that monitor whether the cell's genetic material has repaired any damage and therefore is ready for mitosis, further experiments showed. Irradiation of the cultured cells normally delays cell division until any DNA damage is repaired. But a large fraction of cells expressing mutant Cdc25C bypassed the checkpoint and underwent mitosis after irradiation.

These findings suggest a one-two punch for cancer cells. Patients could receive a drug that disrupts the Cdc25C regulatory pathway to force irradiated cancer cells to divide prematurely, favoring the death of the daughter cells, Piwnica-Worms suggests.

She also identified a class of molecules that may inhibit Cdc25C based on insight by fellow Washington University researcher Andrey S. Shaw, M.D., associate professor of pathology, that these molecules might bind Cdc25C. These 14-33 proteins were known to be involved in the DNA damage checkpoint in certain yeast cells and to participate in many pathways in human cells. Using an antibody, Piwnica-Worms showed that 14-3-3 proteins bound to Cdc25C on the phosphate group at the site that is critical for controlling cell division.

In addition, Piwnica-Worms showed that a yeast protein known as Chk1 (check1) could phosphorylate Cdc25C on the key site proposed to inhibit the protein's mitosis-activating function. Chk1 is a key molecule involved in halting cell division when damage is detected in certain yeast cells.

In a second paper in Science, Piwnica-Worms and collaborators at Baylor College of Medicine showed that a human form of Chk1 could also phosphorylate Cdc25C on the same site, demonstrating the conservation of this regulatory pathway.

Unlike the 14-3-3 proteins, Chk1 acts solely as a cell division regulator in response to DNA damage. So it may be a better target for potential cancer therapies that also involve radiation, Piwnica- Worms notes.

Peng C-Y, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H (1997). Mitotic- and G2 Checkpoint-Control: Regulation of 14-3-3 Protein Binding by Phosphorylation of Cdc25C on Serine 216. Science, 277, 1501-1505.

Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (1997). Conservation of The Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation via Cdc25. Science, 277, 1497-1501.

Washington University in St. Louis

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