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Sugar helps control cell division

Johns Hopkins scientists have discovered that a deceptively simple sugar is in fact a critical regulator of cells' natural life cycle.

The discovery reveals that, when disturbed, this process could contribute to cancer or other diseases by failing to properly control the steps and timing of cell division, the researchers say. The findings are described in the Sept. 23 issue of the Journal of Biological Chemistry, available online now.

The sugar, known as O-GlcNAc (pronounced oh-GLUCK-nack), is used inside cells to modify proteins, turning the proteins off or on, helping or preventing their interactions with other proteins, keeping them from destruction or allowing their destruction. The comings and goings of the sugar on proteins seem to be important controllers of cell division, say the researchers.

"The dogma for decades has been that the cycle of cell division is controlled by the appearance and disappearance of certain proteins called cyclins, but experiments have shown that you can knock out any of these and still get perfectly normal cell division," says the study's first author, Chad Slawson, Ph.D., a postdoctoral fellow in biological chemistry in Johns Hopkins' Institute for Basic Biomedical Sciences. "In contrast, our experiments show that by increasing or decreasing the amount of sugar attached to proteins, the cell cycle is disrupted and isn't salvageable unless O-GlcNAc levels are fixed."

In experiments with human cells and mouse cells, Slawson and his colleagues showed that preventing a cell from removing the sugar from proteins causes the cell to copy its genetic material and make new nuclei, but to fail to divide in two. The end result is cells with more than one nucleus -- a situation fairly common in cancer cells.

"Cells with more than one nucleus can survive, but they are dysregulated -- things just don't go right," says Slawson. "The longer they survive, the worse it gets."

On the other hand, cells th at had higher than normal amounts of the enzyme that removes the sugar from proteins ended up with nuclei that didn't look right under a powerful microscope. Instead of being disseminated fairly uniformly through the entire nucleus, the genetic material of these cells was bunched up, giving the contents of the nucleus a "wrinkly" appearance.

Exactly what is going wrong is still unclear, adds Gerald Hart, Ph.D., professor and director of biological chemistry. He's been studying O-GlcNAc since his lab discovered it attached to proteins inside cells 20 years ago. They now know which enzymes put the sugar onto proteins and which enzymes take it off -- and knocking out or blocking these enzymes allowed the researchers to control whether proteins were sugar-laden or sugar-free.

"Normally, the enzyme that adds the sugar to proteins is enriched at the hub of activity during cell division," notes Slawson. "When we knock it out or block it with a chemical, the cell cycle lengthens and cell division doesn't happen properly. Clearly the enzyme is there for a reason."

But understanding what the sugar itself is doing and how its presence on or absence from proteins affects the cell depends solely on what protein it's being attached to or removed from.

"Whether it's turning something on or off depends on the protein to which the sugar is attached," says Hart. "It's harder than having discovered an enzyme that does just one thing. To figure out the sugar's effect, we have to look at what it's modifying, and the extent and the location of the modification."

The sugar seems to modify as many proteins as the ubiquitous phosphate groups widely recognized as protein controllers, and it frequently seems to compete with phosphate groups for the same spots on proteins. Hart suggests that a particular balance between O-GlcNAc and phosphates on proteins may help fine-tune their activities.

The researchers' next steps are to examine select prote ins modified by O-GlcNAc and found at locations important for various steps in cell division to figure out why an imbalance of O-GlcNAc on the cells' proteins has such a dramatic effect on the process.

The researchers were funded by the National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute.

Authors on the paper are Slawson, Natasha Zachara, Keith Vosseller, Win Den Cheung, Daniel Lane and Gerald Hart, all at Johns Hopkins while working on this project. Vosseller is now at Drexel University.

O-GlcNAc modification of proteins is detected using an antibody developed at Johns Hopkins. Under a licensing agreement between Covance Research Products, Sigma Chemical Company and The Johns Hopkins University School of Medicine, Hart receives a percentage of royalties received by the university on sales of this antibody (CTD 110.6). The terms of this arrangement are being managed in accordance with the university's conflict of interest policy.


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Source:Johns Hopkins Medical Institutions


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