August 25, 2011

Aliquots — research highlights from VUMC laboratories


Brain protein’s role in stomach cancer

Gastric cancer is one of the most common cancers worldwide. While some chemotherapy drugs are initially successful at controlling the tumors, most gastric cancers develop resistance.

Previously, Wael El-Rifai, M.D., Ph.D., and colleagues found that DARPP-32, a protein abundant in neurons and most commonly associated with addiction, is overexpressed in two-thirds of all gastric cancers. The protein is also overexpressed in several other cancer types and appears to inhibit gastric cancer cells’ ability to commit “suicide” (apoptosis).

The researchers have now investigated the involvement of DARPP-32 expression in the resistance of gastric cancer cells to gefitinib (Iressa). They report in the journal Gastroenterology that DARPP-32 enhances survival of cultured gastric cancer cells and increases resistance to gefitinib by promoting activity of the epidermal growth factor receptor (EGFR) pathway. In mice, reducing DARPP-32 in gastric cancer cells led to smaller tumors with increased response to gefitinib. The results suggest that therapies that reduce DARPP-32 activity may be helpful in preventing resistance to this important targeted therapy.

Melissa Marino


Starvation diet kills staph bacteria

One of the ways humans combat invading pathogens – such as Staphylococcus aureus (“staph”) – is by hiding nutrients that are essential to their growth.

Eric Skaar, Ph.D., M.P.H., Walter Chazin, Ph.D., and colleagues previously demonstrated that the protein calprotectin sequesters manganese and zinc and inhibits staph growth. Now, the team has discovered that by binding manganese, calprotectin inhibits staph’s defenses against superoxide, a toxic compound that the immune system uses to destroy microbes. They found that calprotectin increases superoxide levels and enhances the ability of neutrophils (immune cells) to kill staph. The researchers also showed that calprotectin’s metal binding is essential to its antimicrobial properties.

Because similar superoxide defense systems are found in a wide range of bacterial pathogens, calprotectin may also enhance the sensitivity of those microbes to superoxide. The findings, reported Aug. 18 in Cell Host & Microbe, suggest that it may be possible to develop therapeutics that kill microbes by starving them of essential nutrients.

Leigh MacMillan


Keep left, protein says

Despite appearing outwardly symmetrical, the brain actually exhibits many structural and functional asymmetries. The habenular nuclei, brain regions involved in functions ranging from aversive learning to reproduction, show marked asymmetry in size, anatomy and gene expression.

In zebrafish, the habenular nuclei contain dense axons and dendrites (neuropil) on the left side only. This anatomical feature is correlated with increased expression of the protein Kctd12.1 on the left. Joshua Gamse, Ph.D., and colleagues investigated the role of Kctd12 proteins in the left-right asymmetry of this brain region in zebrafish. 

In the July 6 Journal of Neuroscience, they report that Kctd12.1 interacts with another protein Ulk2, which promotes neuropil growth. Reducing Ulk2 expression (or increasing Kctd12 expression) reduces neuropil, while overexpression of Ulk2 (or loss of Kctd12 expression) enhances neuropil, suggesting that Kctd12 proteins limit Ulk2 activity. The findings represent a regulatory mechanism that may underlie the development of asymmetry in this brain region and others.

Melissa Marino


Misfolded protein causes nerve damage

Charcot-Marie-Tooth disease (CMTD) – the most common inherited disease of the peripheral nervous system – results from defects in the myelin coating of nerve cells and slowed electrical conduction.

Charles Sanders, Ph.D., Kevin Schey, Ph.D., and colleagues are using structural and proteomic studies to examine how mutations in peripheral myelin protein 22 (PMP22) cause CMTD. They previously demonstrated that the TrJ mutation in PMP22 reduced protein-folding stability, relative to the wild-type protein. Now, in the Aug. 10 issue of Structure, they report that the TrJ mutation disrupts the protein’s first membrane-spanning domain (TM1), causing it to dissociate from the core of the protein. This destabilization makes TM1 available for recognition by the cell’s protein-folding quality control machinery, which leads to loss of function and formation of toxic aggregates that may play a role in the myelin defects of CMTD.

The TrJ mutation (insertion of a proline residue into a membrane-spanning domain) is a common type of disease-causing mutation, suggesting that other mutant proteins might share the structural folding defects observed in PMP22.

Leigh MacMillan


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:

Past Aliquots

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