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Mutation in tumor suppressor gene causes pancreatic islet cells to reproduce

Cancer biology discovery could lead to new diabetes treatment

Researchers at the University of Pennsylvania School of Medicine have found that the acute loss of a protein called menin can cause the proliferation of pancreatic islet cells, which secrete insulin to regulate blood sugar. The menin gene (Men1) mutation in humans causes an inherited disease called Multiple Endocrine Neoplasia type 1 (MEN1). Not only could this discovery inform basic cancer biology, it also has implications for treating Type 1 diabetes. The researchers report their findings in the latest issue of Cancer Research.

Comparison of islet cell proliferation in pancreatic islets with (left panel) and without (right panel) menin protein. The pink dots within the dashed yellow circle -- indicated by the red arrows -- represent proliferating islet cells. More proliferating cells (pink dots) appear in islets without menin (right). Credit: Ya-Xiong Chen, Ph.D., University of Pennsylvania School of Medicine, and Cancer Research, June 2006

MEN1 patients develop mostly benign tumors or hyperplasia (over proliferation of cells) in several endocrine organs, such as parathyroids and pancreatic islet cells. Normally, the menin protein has a tumor-suppressing or cell-proliferation-suppressing function. Loss of menin can cause proliferation of pancreatic islet cells, but not the adjacent exocrine cells that secrete proteins other than insulin.

The researchers developed an animal model that allowed for precise timing in "cutting" the Men1 gene from the genome of knock-out mice. They showed that within seven days of excising Men1, pancreatic islet cells proliferated in the mice. Previously, other labs could only see proliferating islet cells after months of Men1 excision because they could not precisely time the process. "Our results show an acute effect of Men1 excision and directly link Men1 to repression of pancreatic islet cell proliferation," says senior author Xianxin Hua, MD, PhD, Assistant Professor of Cancer Biology at Penn's Abramson Family Cancer Research Institute.

The researchers excised Men1, the gene encoding the protein menin, from both islet cells and adjacent exocrine cells in the pancreas, but only in islet cells did they observe cells proliferating. This is important because Men1 mutations largely cause endocrine hyperplasia or tumors, but not exocrine tumors. "Our results showing preferential effects on islet-cell proliferation could at least in part explain that the loss of menin only leads to endocrine tumors," explains Hua.

In type I diabetes, the loss of islet beta cells is the leading reason why a sufficient amount of insulin cannot be produced. "If we could eventually repress menin function to specifically stimulate beta-cell proliferation, this may facilitate devising new strategies to increase insulin-secreting beta cells and treating diabetes," notes Hua.

"We did not expect the connection between a study about a tumor suppressor and a potential new avenue for treating diabetes," he adds. "By taking advantage of studying a genetically well-characterized tumor syndrome, MEN1, we set out to understand how the first step of benign tumor development is precisely controlled. The more we discovered about menin function, the better we understood the precise role of menin in regulating islet cell proliferation. This latest finding about the acute and specific role of menin on repressing islet cells, but not adjacent exocrine cells, led to the realization that manipulating the menin pathway might be a powerful way to stimulate islet cell proliferation to fight type I diabetes, although we are just beginning toward that goal."

Study co-authors are Robert B. Schnepp, Ya-Xiong, Haoren Wang, Tim Cash, Albert Silva, Alan Diehl, and Eric Brown, with participation from the members of Dr. Eric Brown's lab and Dr. Alan Diehl's lab, all from Penn. This research was funded by the National Institutes of Health.

Karen Kreeger | EurekAlert!
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