Penn Medicine News Bites

Reversing Diabetes in Mice

2010-11-10T14:27:00-05:00

Researchers have found a novel way to reverse established diabetes in mice, and in the process, unraveled an approach that could potentially be exploited to treat pre-existing diabetes in humans.

Men1 excision dramatically increases a marker of pancreatic beta cell proliferation (orange dots). Click to view full-size image with comparison. Credit: Yuqing Yang, MD, PhD, University of Pennsylvania School of Medicine

Xianxin Hua, MD, PhD, associate professor of Cancer Biology at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine, and colleagues report in the Proceedings of the National Academy of Sciences, that deletion of the Men1 gene, which encodes the protein menin, reversed pre-existing high blood sugar in mice with diabetes. What’s more, the Men1 deletion also ameliorated the pre-existing high blood sugar and glucose intolerance (a condition of pre-diabetes) in mice with inherited diabetes, as well as reversed pre-existing glucose intolerance in high-fat-diet-fed mice, a model mimicking human type 2 diabetes.

These findings in three different models of diabetes point to the fact that improved glucose metabolism happens at least partly by increasing the number of functional beta cells and increasing the size of islet cells. Hua says that the study shows, above all, that established hyperglycemia can be reversed through repression of a single gene, versus classic approaches on prevention of development of diabetes after a gene is deleted. These novel findings strongly suggest that menin is a vital regulator in pathogenesis of diabetes, and importantly a potential new target to treating diabetes.

Other Penn researchers who have contributed to these studies are Yuqing Yang, Buddha Gurung, Haoren Wang, Wing Wu, and Doris Stoffers.

Fighting Leukemia Notch by Notch

2010-11-09T07:53:45-05:00

Two is not always better than one, especially in the case of what causes one type of leukemia.

Dimeric Notch signaling complex on DNA. The purple represents two Notch molecules interacting together with the other members of the transcriptional acitvation complex (CSL-orange, Mastermind-yellow) on DNA. Credit: Lili Guo, University of Pennsylvania School of Medicine

The lab of Warren Pear, MD, PhD, professor of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine, is the first to show that the coming together of two proteins in a process called dimerization is a key step in causing cancerous cell replication in certain tumors in mice.

Previous work from the Pear lab and others has shown that molecular signals associated with the protein, called Notch, is required for the proper development of white blood cells, in particular T cells. Notch signals must be precisely controlled as mutations in Notch that cause increased signaling occur in the vast majority of T-cell acute lymphoblastic leukemias, which make up about 15 to 20 percent of childhood leukemias. Growth of these leukemias can be stopped in mice using new kinds of Notch pathway inhibitors. T-cell leukemia is driven by strong Notch signals and do not arise if Notch can’t dimerize. However, inhibiting Notch dimerization allows other Notch-dependent functions to occur, such as T-cell development. This suggests that dimerization inhibitors may block a subset of Notch functions, such as leukemia induction, without causing the toxicity of the current generation of wider-acting Notch inhibitors. The Pear team describe their findings in Genes & Development.

Splicing Master Switch Impairs Cell Motility and May Prevent Cancer Spread

2010-11-09T07:00:00-05:00

Investigation of a process called alternative splicing is a primary focus of research in the lab of Russ P. Carstens, MD, associate professor of Medicine in the University of Pennsylvania School of Medicine. In recent studies, his group has implicated this process in key steps of cancer progression.

ESRP proteins regulate epithelial-specific splicing. In epithelial cells binding of ESRP proteins downstream of an exon promotes its splicing, whereas ESRP binding upstream of or within an exon causes exon skipping (left). ESRP expression is turned off during the EMT and the resulting switch in splicing produces protein isoforms that contribute to the cellular changes that result in mesenchymal cells with increased migration (right). Russ P. Carstens, MD, University of Pennsylvania School of Medicine

Most solid tumors arise from epithelial cells that line the surface of organs and body cavities. When these tumor cells maintain their epithelial characteristics, they are less likely to spread to distant sites. Epithelial cells can be induced to undergo a change characterized by an increase in motility through a process called the epithelial to mesenchymal transition (EMT).

Though EMT is a critical process during the development of embryos, it can be aberrantly reactivated in tumors, contributing to cancer metastasis. In cancer, when certain molecular switches are turned off or absent, tumor cells acquire characteristics of mesenchymal cells and gain the ability to migrate away from the primary tumor.

An important master-switch that is turned off during the EMT is called the epithelial splicing regulatory protein (ESRP). Proteins in this family are able to change how pre-messenger RNAs (pre-mRNA) produced from genes are spliced together in different ways so that there can be more than one mRNA derived from a single gene. These mRNAs go on to code for proteins that often demonstrate opposing functions.

Carstens and Claude Warzecha, PhD, a postdoc in the Carstens’ lab, recently collaborated with Yi Xing’s group at the University of Iowa and Wei Guo’s lab from the Biology Department at Penn in a study published in The EMBO Journal that identified a network of hundreds of alternative splicing events within genes that act to control cell migration. These splicing changes were all controlled by ESRP proteins, suggesting they are true master regulators required to maintain epithelial cell properties. When the ESRPs are turned off in epithelial cells, the cells change shape, have increased migration, and demonstrate other hallmarks of the EMT. An important implication of this work is the ESRP-regulated “splicing signature,” which represents a biomarker that can be used to classify cancer cell types so may have important diagnostic and prognostic implications for human cancers. What’s more, identification of compounds that can restore ESRP expression may guide the development of future cancer therapies targeted at preventing or slowing metastasis.