March 2, 2007

Aliquots — Research highlights from VUMC laboratories

Featured Image

Snapshot of a genetic “editor”

The structure of the large, dynamic molecular machine known as the spliceosome has been difficult to get a handle on.

Acting as a genetic “editor,” the spliceosome excises introns (non-coding regions) from the uncorrected “hardcopy” of DNA transcription (pre-mRNA) to produce an RNA molecule that makes sense when translated into protein. During this splicing process, this hulking complex — composed of several ribonucleoproteins and hundreds of other protein molecules — continually assembles and disassembles, making it difficult to visualize.

Using cryoelectron microscopy, Kathleen Gould, Ph.D., and colleagues have determined the 3D structure of a spliceosome complex isolated from the yeast Schizosaccharomyces pombe. In the Feb. 20 Early Edition of the Proceedings of the National Academy of Sciences, Gould and colleagues provide a detailed description of the structure of this asymmetric particle involved in the late stages of pre-mRNA splicing.

Having a snapshot of this macromolecule is an important step toward understanding the splicing process, which is vital to the normal production of proteins and cellular function.

— Melissa Marino

Ups and downs of cancer invasion

Two colon cancer proteins are linked in a seesaw relationship, a team of surgical oncology investigators has found. When one goes up, the other goes down, with the cancer's invasive or metastatic capacity teetering in the balance.

Loss of the tumor suppressor protein Smad4 correlates with increased invasiveness of colon tumors. Punita Dhawan, Ph.D., and colleagues report in the Feb. 15 issue of Cancer Research that Smad4 regulates expression of a metastasis-promoting protein called claudin-1. The investigators had previously demonstrated that claudin-1 expression increases during colon carcinogenesis, particularly in metastatic colorectal cancer. Now they've linked the claudin-1 increase to loss of Smad4.

The researchers confirmed that expression of Smad4 reduces levels of claudin-1, and that this reduction in claudin-1 contributes to the ability of Smad4 to inhibit invasion in colon cancer cells. Smad4 is a central component of signaling for the growth factor TGF-beta, but Smad4's effects on claudin-1 are not due to modulation of TGF-beta signaling, Dhawan and colleagues found. Understanding how Smad4 functions as a tumor suppressor may point to new therapeutic targets in colon cancer.

— Leigh MacMillan

Dead ends in the bibliography

Citing internet addresses, or URLs (Uniform Record Locators), in reference sections of biomedical research papers is becoming increasingly common. But just how reliable are those links?

Dominik Aronsky, M.D., Ph.D., and colleagues analyzed the prevalence and accessibility of URLs cited in the bibliographies of biomedical articles recently posted on PubMed. In the current edition of the Journal of the American Medical Informatics Association, they report that 11.9 percent of cited URLs were inaccessible just two days after an article's release to the public (on PubMed).

Though the researchers did not determine the reasons for inaccessibility, this high error rate suggests that authors may need to be particularly careful when citing a URL in their bibliography.

— Melissa Marino

Viagra points to diabetes prevention

The drug that has improved many love lives has revealed a possible new therapeutic target for treating insulin resistance — a condition that often leads to metabolic syndrome and type 2 diabetes. Julio Ayala, Ph.D., David Wasserman, Ph.D., and colleagues report in the journal Diabetes that sildenafil (brand name Viagra) improves a number of measures of insulin sensitivity in mice with diet-induced insulin resistance.

The researchers fed mice a high-fat diet for 12 weeks to induce obesity and insulin resistance. Mice treated with sildenafil for the duration of the experiment showed reduced weight and fat mass, increased energy expenditure, lower fasting insulin and glucose levels, and enhanced rates of glucose infusion, disappearance and muscle glucose uptake.

Since sildenafil improved energy balance and insulin action without adversely affecting blood pressure or cardiac morphology, the study suggests that PDE5 — the enzyme inhibited by sildenafil — could be a potential target for therapies to prevent insulin resistance and, potentially, diabetes.

— 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