In 2004 we demonstrated that O-GlcNAcylation of intracellular proteins was a novel regulator of cell survival and a modulator of the cellular stress response. In response to diverse forms of cellular stress, the O-GlcNAc modification is increased on myriad proteins. Elevation of O-GlcNAc levels prior to or after the induction of injury promotes cell survival in models of heat stress, hypoxia, oxidative stress, ischemia repercussion injury, and trauma hemorrhage. Conversely, lowering O-GlcNAc levels sensitizes cells to various forms of injury. Together, these data suggest that modification of proteins by O-GlcNAc in an integral component of the cellular stress response.
Elevation of O-GlcNAc levels modulates numerous pathways in a manner consistent with increased cell survival, including the expression of heat shock proteins. However, the molecular mechanisms by which O-GlcNAc promotes cell survival are unknown. Our laboratories goal is to understand the O-GlcNAc regulated stress response, how this can be manipulated to improve patient outcome, and how this response is misregulated in disease.
Above: Biosynthesis of O-GlcNAc and Impact on Cellular Pathways associated with survival.