July 18, 2008

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.

A spiny problem at the synapse

Dendritic spines – tiny protrusions on the branched neuronal projections known as dendrites – form connections, or synapses, with the axons of other neurons. Changes in synapse number and strength underlie learning and memory. While the size, number and shape of dendritic spines change rapidly to alter synapses, the molecular signals that regulate this metamorphosis are unclear.

In the June 6 Journal of Biological Chemistry, Donna Webb, Ph.D., and colleagues demonstrate key roles for proteins that regulate the actin cytoskeleton, the cell’s internal scaffold, in this process. One protein, called N-WASP, localized to spines and synapses in neurons from the rat hippocampus, a brain structure central to learning and memory. Reducing N-WASP expression or activity decreased the number of spines and synapses, as did interfering with its interaction with the Arp2/3 complex – a protein complex associated with actin. The results reveal crucial roles for N-WASP and the Arp2/3 complex in the ever-changing nature of dendritic spines.

— Melissa Marino

Found: a signaling partner for Bves

The protein Bves – blood vessel epicardial substance – is something of a mystery. It is widely expressed during development and in adulthood in many different species, and has been suggested to have a role in cell-cell interactions, but its precise molecular function is unknown.

To probe Bves function, David Bader, Ph.D., and colleagues, searched for Bves-interacting proteins and identified GEFT (guanine nucleotide exchange factor T). GEFT is a protein that modulates the activities of the small GTPase proteins Rac1 and Cdc42, which participate in cell proliferation, differentiation, motility and gene expression. The investigators found that expression of a shortened form of Bves in cultured cells reduces Rac1 and Cdc42 activities, decreases cell motility, and increases cell roundness. The results, reported in the June 17 Proceedings of the National Academy of Sciences, suggest that Bves, through its interaction with GEFT, is a novel regulator of the Rac1 and Cdc42 signaling cascades.

— Leigh MacMillan

Stroke associated with some painkillers

Coxibs, the selective cyclooxygenase 2 (COX-2) inhibitors initially designed to avoid the gastrointestinal problems caused by traditional non-steroidal anti-inflammatory drugs (NSAIDS), have suffered a series of setbacks. Two coxibs – rofecoxib (Vioxx) and valdecoxib (Bextra) – were withdrawn from the market due to adverse cardiovascular affects. Questions remain, however, about the safety of another popular drug, celecoxib (Celebrex), and other nonselective NSAIDs (like ibuprofen and naproxen).

Christianne Roumie, M.D., M.P.H., and colleagues analyzed medical records of 336,906 Tennessee Medicaid enrollees from 1999 to 2004 (before the drug withdrawals) to determine whether coxibs and traditional, nonselective NSAIDs increased stroke risk. In the July issue of Stroke, they report that neither celecoxib nor traditional NSAID use was associated with a higher risk of stroke. However, rofecoxib and valdecoxib did increase stroke risk, suggesting that these drugs should not be reintroduced into the market. Since all NSAIDs, including coxibs, can raise blood pressure and increase the risk of gastrointestinal bleeding, caution is warranted, especially with long-term use of these medicines.

— William Peters

Blueprints for a circadian clock

Circadian clocks are biological timekeepers, regulating the metabolic, physiological and behavioral aspects of life on a nearly perfect 24-hour cycle. Blue-green algae (cyanobacteria) are the simplest organisms known to have such a clock, which can be reconstituted in vitro from three proteins: KaiA, KaiB and KaiC. Martin Egli, Ph.D., and colleagues have been characterizing this clock system, determining the molecular structures of the clock components and fitting them together like pieces of a jigsaw puzzle. Previously, they assembled a model of the KaiA-KaiC complex.

In the June 18 issue of The EMBO Journal, the researchers now provide a three-dimensional model of the KaiB-KaiC complex, demonstrating how these proteins interact and how adding and removing phosphate groups from KaiC (functions of KaiA and KaiB, respectively) alters the structure of the complex. When considered together with the KaiA-KaiC model, this new model suggests mechanisms by which KaiB counteracts the actions of KaiA and may explain how particular sections of each component interact to keep the clock ticking.

— 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