Sugar helps control cell division

September 20, 2005

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 that 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 proteins 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.
-end-
On the Web: http://www.jbc.org/cgi/reprint/M503396200v1

Johns Hopkins Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.