D. Brent Polk, M.D., is studying a protein that may one day have an impact on the treatment of inflammatory bowel disease.
photo by Anne Rayner
Protein offers ‘stay of execution’ for inflamed bowels
In the inflamed intestines of a patient with inflammatory bowel disease (IBD), the body's own immune system commands the cells lining the intestinal tract to commit suicide.
Recently, Vanderbilt University Medical Center researchers identified a life-preserving protein that seems to rescue these cells from an almost certain death.
The protein, called kinase suppressor of Ras-1 (KSR1), protects the intestine by turning on survival pathways inside the cells. This discovery suggests that KSR1 could be a novel therapeutic target for inflammatory bowel disease as well as certain types of gastrointestinal cancers.
The study, led by D. Brent Polk, M.D., professor of Pediatrics and Cell and Developmental Biology, was published in the November issue of the Journal of Clinical Investigation.
Inflammatory bowel disease, a group of conditions that includes Crohn's disease and ulcerative colitis, affects nearly 1 million Americans. These conditions are characterized by chronic inflammation (redness and swelling) of the digestive tract. In IBD, an overactive immune response churns out heaps of pro-inflammatory proteins, which prompt the epithelial cells lining the intestines to commit suicide.
“Clearly, not all the intestinal cells die (in IBD),” Polk said. “The question that we were asking is 'what are the factors that regulate intestinal cell survival in an inflammatory environment?”
One pro-inflammatory protein that is produced in large amounts is tumor necrosis factor (TNF). TNF can act as either a survival or death signal depending on the activation of other cellular proteins, including KSR1.
Polk and colleagues used several different animal models to investigate the role of TNF and KSR1 in the fate of intestinal cells.
Polk first examined KSR1 activity in mice that lack an anti-inflammatory protein called interleukin-10 (IL-10) — a standard model of IBD. These mice produce high levels of TNF and show increased inflammation and death of intestinal cells.
“When we looked at those mice which had IBD, KSR1 was activated,” Polk said. “Not only was KSR activated, but the cell survival pathways were also activated with inflammation.” This showed that KSR1 likely jump-starts the cell survival machinery, in order to protect the cell from impending death.
In another model, Polk injected TNF into mice that lacked KSR1. The cell survival pathways did not become active. However, the cell death pathways were fully activated, again suggesting that KSR1 regulates the life-or-death decisions prompted by TNF.
In a final set of experiments, Polk bred the two mutant strains of mice together to form a genetic cross lacking both IL-10 and KSR.
“Our thinking was that … if we had exaggerated TNF production (as in the IL-10 deficient mouse) and also lacked KSR1, we would expect to see increased cell death. And that's what we saw. “
With the results of the three experiments, Polk and colleagues have provided mounting evidence that KSR1 is a master switch that promotes cell survival in the face of inflammation. Thus, activating KSR1 with drugs could protect intestinal cells from inflammation-induced death, providing a novel approach to treating IBD.
Since proteins like KSR1 are activated by the addition of phosphate groups, a process called (phosphorylation), Polk is currently working on identifying these phosphorylation sites within KSR1.
“If we can identify the required phosphorylation sites, then it is feasible to develop small molecules (drugs) that interfere with that phosphorylation and activation,” he said.
However, it's a tenuous balance between protecting cells from death and promoting their unchecked proliferation. As Polk noted, there is an increased incidence of colon and other gastrointestinal cancers in patients with IBD.
“The potential cost is that KSR1 also may be a target for development of tumors because it promotes the cell's ability to survive in a chronic inflammatory environment.”
In a state of chronic inflammation, like in IBD, these continuous pro-survival signals may be too much of a good thing. Activating KSR too much could potentially promote tumor formation.
Genetic screens in the microscopic worm, C. elegans, and fruit flies have shown that mutations in KSR1 interfere with Ras, a protein that is commonly activated in colon and other epithelial cancers. In future studies, Polk will investigate this link in mouse models of colon cancer.
“It might turn out rather than activating (KSR1) to treat IBD, it may be a better target for inhibition in certain cancers,” Polk said.
Other Vanderbilt authors on the study were Fang Yan, Sutha K. John, Guinn Wilson, David S. Jones, and M. Kay Washington. The research was funded by the Crohn's and Colitis Foundation of America and the NIH.