March 5, 2010

Aliquots — research highlights from VUMC laboratories


Protein suppressor of colon tumors

Colorectal cancers appear to require a series of genetic alterations in the cells lining the colon. In the Journal of Clinical Investigation, James Goldenring, M.D., Ph.D., and colleagues report that expression of Rab25 – a protein known to regulate protein trafficking within the cell – may play a role in early colon tumor development.

In two groups of colorectal cancer patients, the investigators found that tumors had substantially decreased Rab25 expression compared with normal colon and that lower Rab25 expression levels predicted poorer survival. To confirm a role for Rab25 in colorectal tumor formation, the investigators generated mice lacking Rab25 and bred them with two different strains of mice that are prone to developing colon polyps and tumors. They found that Rab25-deficient mice developed more intestinal polyps and colon tumors than parental mice.

The findings suggest that Rab25 may act as a tumor suppressor in the colon lining and that reduction of Rab25 expression may be an early event in colon cancer formation.

— Melissa Marino


Gene defect’s role in muscle disease

Myotonic dystrophy type 2 (DM2) is a form of muscular dystrophy caused by a genetic alteration in the ZNF9 gene, whose product is believed to function as an RNA-binding protein. But whether ZNF9 function actually plays a role in the mechanism of this disease has been controversial.

In examining the normal function of ZNF9 in cultured cells, Andrew Link, Ph.D., and colleagues found that ZNF9 interacts with ribosomes – protein complexes responsible for translation (the production of protein from mRNA) – and regulates a specific type of translation, called cap-independent translation.

The researchers then examined ZNF9 function in normal human muscle progenitor cells (myoblasts) and in myoblasts from a patient with DM2. They found that ZNF9 can activate cap-independent translation in these cells and that this activity is reduced in myoblasts from the DM2 patient.

The results, published in PLoS ONE, suggest that loss of ZNF9 activity in muscle cells may contribute to symptoms of this disorder – which include muscle weakness, cardiac anomalies and cataracts.

— Melissa Marino


Amino acid amiss in inflamed colon

Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD) characterized by recurrent inflammation of the colon’s mucosal cell layer, causes abdominal pain and diarrhea. Studies have suggested that metabolism of the amino acid L-arginine (L-Arg) may be altered in ischemic colitis and IBD. To explore the hypothesis that L-Arg is dysregulated in UC, Keith Wilson, M.D., and colleagues examined serum L-Arg levels and disease severity in patients with UC.

They report in the January issue of Inflammatory Bowel Diseases that serum L-Arg levels correlated with UC disease severity (L-Arg levels were higher in patients with more severe UC, scored by histopathology and endoscopy). However, L-Arg was not more available to mucosal cells, because levels of other amino acids that compete with L-Arg for cell entry were also higher in patients with severe disease.

The findings suggest that L-Arg uptake by cells in the inflamed colon is defective, which may contribute to the pathogenesis of UC and could suggest new treatment options.

— Leigh MacMillan


Lasting legacy of early-life stress

Stress – such as abuse or trauma – early in life can lead to anxiety and depression in adulthood. How early-life stress influences behavior in adults is unclear, but previous studies have implicated corticotropin-releasing hormone (CRH) – one of the body’s main stress hormones – in this process.

To test the hypothesis that CRH in the developing forebrain increases anxiety and depression in adult animals, Louis Muglia, M.D., Ph.D., and colleagues increased CRH expression in the mouse forebrain during embryonic development through three weeks after birth. They found that this early-life increase in CRH exposure increased anxiety and depression-like behaviors in adult mice. The behavioral changes were associated with increased levels of the CRH type 1 receptor and were reversed by treatment with the anti-depressant imipramine.

The findings, reported in the Feb. 17 Journal of Neuroscience, suggest that pharmacological blockade of CRH receptors may prevent high-risk patients from developing psychiatric illness. The mice will provide a useful model for testing this and other ways to prevent the long-term consequences of childhood stress.

— 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