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 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.
"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.
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.
Source: Journal of Biological Chemistry