Aliquots — research highlights from VMC laboratories

3/06/2009 - We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.

 

Liver target for diabetes

The liver – which both produces and takes up glucose – plays a significant role in controlling blood glucose and, consequently, the development of diabetes. Glucokinase (GK), a liver enzyme that regulates blood glucose levels, is considered an important target for drugs to treat type 2 diabetes. Previously, Masakazu Shiota DVM, Ph.D., and colleagues showed that early diabetic changes in male Zucker diabetic fatty rats – a model of obesity-related type 2 diabetes – were associated with impaired regulation of GK.
In the January issue of Diabetes, the researchers show that GK expression in the liver progressively decreases as diabetes progresses in these rats – GK activity was only 30 percent of normal at 20 weeks of age. Using a gene therapy approach, they show that normalizing liver GK restores plasma glucose to near normal levels. The results suggest that maintaining GK activity in the liver – either by gene therapy or pharmaceutical intervention – could represent a therapeutic approach to regulating glucose levels in type 2 diabetes.

— Melissa Marino

 

Heartbeat clues from worms

The potassium channel HERG plays a key role in maintaining the rhythmic heartbeat. Mutations in the HERG gene, or drugs that block the channel, can cause long QT syndrome (LQTS) and life-threatening cardiac arrhythmias.

Sabina Kupershmidt, Ph.D., and colleagues have been searching for proteins that regulate the HERG channel – these factors may have therapeutic potential for LQTS. Using a C. elegans-based screening tool they developed, the investigators have identified a new regulator of HERG: the worm “cousin” of human rho-GTPase activating protein 6 (ARHGAP6). Using cultured cells, they showed that ARHGAP6 reduced both potassium current and HERG protein on the cell surface by activating a phospholipase C signaling pathway. They also blocked ARHGAP6 in cardiac cells and demonstrated enhanced potassium current, consistent with a negative regulatory role for ARHGAP6. The findings in the February Journal of Molecular and Cellular Cardiology implicate ARHGAP6 and associated signaling proteins as candidate genes in disorders involving HERG, such as LQTS.

— Leigh MacMillan

 

Kidney fix-it factor

Acute kidney injury – from exposure to chemotherapy or immunosuppressive drugs, for example – is common, but the mechanisms of injury and repair are poorly understood.

To test the hypothesis that the protein NFATc1 might play a role in the regeneration of kidney cells after injury, H. Scott Baldwin, M.D., and colleagues induced kidney injury in control mice and in mice lacking one copy of the NFATc1 gene. They report in the February Journal of the American Society of Nephrology that the NFATc1-deficient mice had increased kidney cell death, sustained injury and delayed regeneration compared to control mice. Treatment with the immunosuppressant drug cyclosporin A, which further reduces NFATc1 activity, increased the renal injury. Using transgenic NFATc1 mouse models, the researchers identified a subpopulation of kidney cells with enhanced NFATc1 expression after injury. These cells were resistant to cell death and acted as a progenitor population that divided to repopulate the kidney proximal tubule, supporting a role for NFATc1 in kidney cell regeneration.

— Leigh MacMillan

 

p120’s ROCKing role in tumor cells

Cancer cells have the unique ability to grow even after losing touch with their neighbors. A protein called p120-catenin seems to play an important tumor-suppressing role by regulating the stability of cadherins – proteins that maintain the bonds between normal cells – and also possibly by interacting with the oncogene Src. To further investigate p120’s role in oncogene-mediated transformation, Albert Reynolds, Ph.D., and colleagues examined p120’s impact on anchorage-independent growth (AIG), an in vitro test that correlates with tumorigenicity in vivo, induced by oncogenes Rac1, Src and H-ras.
In the Feb. 9 Journal of Cell Biology, they report that p120 loss blocks Rac1- and Src-induced AIG by suppressing a key signaling pathway (RhoA-ROCK pathway). H-ras induced AIG was not affected by p120 loss. However, all three oncogenes depended on ROCK suppression, suggesting that ROCK may act as a gatekeeper for activities essential for AIG, and therefore, tumor development. The results demonstrate for the first time a clear requirement for p120 in oncogene-mediated tumorigenesis.

— Melissa Marino

Past Aliquots

Feb. 5, 2010
Jan. 22, 2010
Jan. 8, 2010
Dec. 11, 2009
Nov. 20, 2009
Nov. 6, 2009
Oct. 23, 2009
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