April 4, 2008

Aliquots — Research highlights from VUMC laboratories

Featured Image

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.

Aglow in the gut

The enteric nervous system (ENS) – the “brain” of the gut – controls motility, mucosal transport, tissue defense and vascular perfusion of the gastrointestinal tract. To investigate how the ENS develops, Michelle Southard-Smith, Ph.D., and colleagues have developed a valuable new tool – a transgenic mouse line in which cells that populate the ENS “glow” a vibrant blue-green.

In the April issue of Developmental Dynamics, the investigators describe and characterize the transgenic mice, which express a fluorescent protein driven by the regulatory regions of Phox2b, a gene expressed in all ENS precursor cells. Because the construct does not alter the endogenous Phox2b locus, it does not interfere with normal ENS development. The studies revealed that – contrary to current models – the neural crest cells that migrate to form the ENS are not a homogeneous group at the start of their journey, suggesting that individual cell fates may be set before markers of mature cell types appear.

— Leigh MacMillan

A break in B-cell lymphoma

Mdm2, a protein that regulates the p53 tumor suppressor, is frequently overexpressed in lymphomas, a type of cancer that originates in blood lymphocytes. However, little is known about how Mdm2 overexpression influences cellular processes in lymphocytes. Using transgenic mice, Christine Eischen, Ph.D., and colleagues examined the effects of elevated expression of Mdm2 in B-cells, the antibody-producing cells affected in B-cell lymphoma.

They found that overexpression of Mdm2 increased proliferation and reduced the susceptibility of B-cells to programmed cell death. In addition, B-cells from these mice had increased frequency of chromosome breaks and often lost or gained one or more chromosomes. These effects set up a “perfect storm” that sparked increased B-cell transformation and accelerated the development of B-cell lymphoma.

The results, published in the March issue of Oncogene, offer a mechanism by which Mdm2 overexpression facilitates B-cell lymphoma development and suggest that targeting Mdm2 in tumors that overexpress the protein could be a potent therapeutic approach.

— Melissa Marino

In search of heart rhythm genes

Atrial fibrillation (AF), the most common cardiac arrhythmia in the United States, carries a substantial risk of stroke and affects more than 2 million people – a number that will climb as the population ages. Some forms of AF have a genetic contribution, but few causal genes have been identified.

Dawood Darbar, M.D., and colleagues analyzed a large family with eight AF-affected members and mapped a novel locus for AF to chromosome 5p15. The investigators also showed that a special kind of electrocardiogram capable of measuring the P-wave duration (signal-averaged ECG) correctly identified both AF-affected individuals and carriers of the AF locus who did not yet have the arrhythmia. Inclusion of these individuals in the genetic analysis strengthened linkage to the chromosome 5p15 locus.

The study, in the March 18 Journal of the American College of Cardiology, supports using signal-averaged ECG to characterize AF in affected families, as a way to accelerate efforts to find disease genes.

— Leigh MacMillan

The making of an antibiotic

The soil-dwelling bacteria Streptomycetes are a blessing to modern medicine, producing more than half of all antibiotics as well as several other medically useful compounds. The genome of one strain, Streptomyces coelicolor, contains an enzyme, cytochrome P450 170A1 (CYP170A1), whose biological function is not yet clear.

Because the gene encoding CYP170A1 abuts another gene whose protein product catalyzes the formation of a novel hydrocarbon, epi-isozizaene, Bin Zhao, Ph.D., and colleagues investigated whether epi-isozizaene was a substrate for CYP170A1.

In the March 28 issue of the Journal of Biological Chemistry, they report that the enzyme catalyzes the conversion of epi-isozizaene to albaflavenone – an earthy-smelling compound with antibacterial properties. The researchers detected albaflavenone and its precursors in S. coelicolor extracts, and showed that disruption of the CYP170A1 gene abolished the synthesis of these compounds with the exception of epi-isozizaene.

The results demonstrate, for the first time, the presence of this antibiotic in S. coelicolor, and reveal important mechanistic insights into its synthesis.

— Melissa Marino

Past Aliquots

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