January 9, 2009

Aliquots — Research highlights from VUMC laboratories

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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.

Proliferate or perish

One of the most frequently activated cancer-inducing oncogenes is c-Myc, a protein essential for cell proliferation. But just how it causes transformation of normal cells into cancer cells is not clear.

Stephen Hann, Ph.D., and colleagues examined whether another protein, called nucleophosmin (NPM) – which is overexpressed in several types of cancer – plays a part in c-Myc’s proliferative and transforming properties. In the Dec.1 Proceedings of the National Academy of Sciences, they report that overexpressing NPM in cultured mouse cells with activated c-Myc dramatically stimulates c-Myc-induced hyperproliferation and transformation. Inhibiting or eliminating NPM expression crippled the ability of c-Myc to induce transformation, suggesting that NPM is a required cofactor for c-Myc’s cancer-promoting activities.

Previously, Hann and others have shown that both c-Myc and NPM bind to various tumor suppressors. Because NPM links the c-Myc proliferative pathway with tumor suppressor pathways, the authors suggest that the balance of NPM, c-Myc and the tumor suppressors that interact with them determine whether a cell will die or become a tumor.

— Melissa Marino

Off-rhythm heart puts babies at risk

Sudden cardiac death from abnormal heart rhythms (arrhythmias) can occur at any age. Recent evidence suggests that nearly 10 percent of sudden infant death syndrome (SIDS) victims have mutations in arrhythmia-susceptibility genes, such as the gene en-coding the cardiac sodium channel, SCN5A.

Dao Wang, M.D., Ph.D., and colleagues, have characterized a novel SCN5A mutation that occurred in two unrelated and ethnically distinct newborns with long-QT syndrome, which predisposed them to severe ventricular arrhythmias before and after birth. The researchers report in the December issue of Circulation: Arrhythmia and Electrophysiology that the new SCN5A mutation causes a profound defect in sodium channel function. They found that the variant channel was more sensitive to mexiletine and propranolol (which were used to treat the infants) than the wild-type channel, and that the two drugs together had an additive effect on the mutant channel.

The study demonstrates the molecular basis for a severe perinatal form of long-QT syndrome. Understanding the genetic risks for perinatal mortality will aid efforts to identify and treat at-risk newborns.

— Leigh MacMillan

Smoking leaves mark in tumor DNA

While smoking is responsible for most lung cancers, lung cancer in non-smokers behaves similarly as in smokers. But researchers think that the molecular pathways in the two groups may differ.

Pierre Massion, M.D., Yong Zou, and colleagues examined genomic alterations in non-small cell lung cancer from three groups of patients: current smokers or recent quitters; former smokers (who had quit two to 22 years before diagnosis); and never-smokers/long-time quitters (who had quit smoking more than 23 years before diagnosis). They found that lung tumors from current smokers had the greatest number of genomic alterations, mostly in areas containing genes involved in the cell cycle, chromosome segregation, and DNA methylation. The findings, reported in the Dec. 1 American Journal of Respiratory and Critical Care Medicine, indicate that smoking leaves an identifiable genomic signature in the DNA of lung tumors. These alterations demonstrate that lung cancers in current smokers are genetically different than those found in non-smokers, which could suggest new targets for cancer treatment.

— Melissa Marino

Sight-stealing role for immune system

Glaucoma, the leading cause of irreversible blindness, is typically associated with chronic elevation of intraocular pressure. But in many individuals, glaucomatous damage to retinal ganglion cells (RGCs) – the neurons whose axons make up the optic nerve – occurs without increased pressure inside the eye.

To explore the idea that autoimmune activity may cause RGC damage, David Calkins, Ph.D., and colleagues induced an immune response in rats by injecting heat shock proteins (HSPs). They report in the Nov. 12 Journal of Neuroscience that HSP27 and HSP60 immunizations resulted in RGC degeneration and axon loss one to four months later, in a pattern similar to human glaucoma. They also observed increased numbers of immune system T-cells in the retina 14 to 21 days after HSP injection and found that T-cells isolated from immunized rats caused programmed cell death of cultured RGCs. The studies describe a novel in vivo tool for examining immune responses in the eye and may facilitate the identification of treatment strategies to prevent RGC degeneration.

— Leigh MacMillan

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012