June 3, 2010

Aliquots — research highlights from VUMC laboratories


Genes work together in prostate cancer

Prostate cancer, the second leading cause of cancer death among men in the United States, may be spurred on by a dramatic synergy between two oncogenes, Sarki Abdulkadir, M.D., Ph.D., and colleagues have found.

In the April 29 issue of Oncogene, they report that these two factors – MYC and PIM1, which have individually been linked to prostate cancer – were co-expressed in 44 percent of human prostate cancers and in 61 percent of high-grade tumors (Gleason grade 4/5). The researchers then developed a mouse “tissue recombination model” to identify the mechanisms by which these factors interact. They found that while PIM1 by itself is weakly tumor-promoting, the combination of PIM1 and MYC induces prostate cancer within six weeks in these mice. Additionally, tumors that co-express MYC and PIM1 showed signs of neuroendocrine differentiation, which in human tumors is associated with poor prognosis.

The results suggest that targeting PIM1 may be an effective and well-tolerated treatment strategy to halt prostate cancer progression.

Melissa Marino


Genomic breadcrumbs for MS risk

Multiple sclerosis (MS), a debilitating disorder that strips nerves of their protective insulation, often strikes at higher frequency within families, suggesting a genetic underpinning. Although several genetic risk “loci” (spots in the genome linked to the disease) have been identified, they tend to involve common variants that account for a small fraction of MS cases.



William Bush, Ph.D., and colleagues in The International Multiple Sclerosis Genetics Consortium now provide statistical evidence for the involvement of hundreds – or perhaps thousands – of genetic risk factors for MS.

In the April 9 issue of the American Journal of Human Genetics, the researchers report their analysis of two independent genome-wide association studies (GWAS), studies that look across the entire genome for variations that associate with certain traits. While the results provide strong evidence that MS risk is likely governed by the cumulative effect of multiple genetic variants scattered throughout the genome, larger GWAS studies are needed to pinpoint the locations of these variants in the genome.

Melissa Marino


Piecing together heart development

Sodium channels – proteins that pass sodium ions across the cell membrane – play a critical role in the electrical activity of cardiac muscle. Mutations in SCN5A, the heart’s main sodium channel gene, are associated with inherited disorders of heart rhythm. However, the function of this sodium channel during development is not understood.

Studying zebrafish embryos, Dan Roden, M.D., Tao Zhong, Ph.D., and colleagues found that two SCN5A-like channels were expressed early in development – even before excitable cardiac tissue forms. Knocking down the expression of either channel reduced the expression of genes associated with cardiac muscle cells and resulted in heart malformations. Blocking sodium current through the channels and growing embryos in sodium-free medium did not cause the same defects, suggesting that the sodium channels have a novel role in early cardiac development that is not linked to their electrical activity.

The findings in the April 30 issue of Circulation Research contribute to an improved understanding of the diverse spectrum of clinical disorders linked to mutations in SCN5A.

Leigh MacMillan


Kidney protective factor identified

The kidney’s core, the renal medulla, is a harsh environment characterized by high oxidative stress. Chuan-Ming Hao, M.D., Ph.D., and colleagues have found that Sirtuin 1 (Sirt1), a protein suggested to have anti-oxidant functions, plays an important protective role in the kidney.

Wellcome Images

Wellcome Images

In the April Journal of Clinical Investigation, they report that Sirt1 is expressed at high levels in the mouse renal medulla. Knocking down its expression in cultured renal cells increased markers of oxidative stress whereas activating Sirt1 with compounds like resveratrol (the component of red wine with reported anti-aging effects) improved cell survival. In a mouse model of kidney ureter obstruction, Sirt1 deficiency increased – and Sirt1 activation reduced – fibrosis and cell death (apoptosis). Sirt1 induction of the enzyme cyclooxygenase-2 appears to contribute to the protective function.

The findings suggest that Sirt1 may be a good therapeutic target for protecting the kidney from oxidative stress-mediated injury and aging-related renal diseases.

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: aliquots@vanderbilt.edu.


Past Aliquots

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