May 25, 2007

Aliquots — Research highlights from VUMC laboratories

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On the way to gastric cancer

The loss of acid-producing parietal cells in the stomach is a critical step in the development of chronic gastritis and gastric cancer. A team led by James Goldenring, M.D., Ph.D., has been tracking the changes in cell types — metaplasia — that accompany parietal cell loss, including the emergence of a metaplastic mucous cell type called SPEM. SPEM has been identified in the majority of stomach fundus biopsies showing Helicobacter pylori-associated gastritis, and it is almost invariably associated with gastric adenocarcinomas.

Parietal cells produce several different epidermal growth factor receptor (EGFR) ligands, which regulate differentiation in the gastric mucosa. The investigators chemically induced parietal cell loss in mice lacking one or another of these ligands and studied the effects on gastric cell types. They report in the May issue of Gastroenterology that absence of the EGFR ligand amphiregulin accelerates the emergence of SPEM, bringing a new factor into the mix of regulators of gastric metaplasia.

— Leigh MacMillan

Cutting out DNA damage

The integrity of a cell's DNA is constantly threatened by chemical attack from a variety of toxins. The ensuing damage, if uncorrected, can cause cell death or trigger tumorigenesis. Luckily, error-correction mechanisms exist to remove and replace damaged DNA bases.

In the May 2 issue of The EMBO Journal, Brandt Eichman, Ph.D., and colleagues present high-resolution crystal structures for 3-methyladenine DNA glycosylase I (TAG), an enzyme that specifically removes 3-methyladenine, a damaged base that results from attack by alkylating agents like many carcinogens. The team found that while structurally similar to related enzymes, TAG uses a unique and unexpected biochemical mechanism to gain access to and remove the damaged base.

Because exposure to carcinogens and some chemotherapeutic drugs can cause this kind of DNA damage, understanding the enzyme's structural and functional properties could help researchers find ways to protect against carcinogens and possibly improve anti-cancer drugs that use such DNA-damaging agents.

— Melissa Marino

DNA-binding protein’s new role

The molecular recipes that direct cellular differentiation require just the right mix of ingredients — specific proteins, in the proper proportions, attached to the appropriate DNA elements.

In the April 15 issue of Genes & Development, Stephen Brandt, M.D., and colleagues identify a new role for single-stranded DNA-binding proteins (SSBPs), which normally act to keep DNA “unraveled” during transcription, in regulating the abundance of proteins involved in red blood cell differentiation. They found that two SSBPs — SSBP2 and SSBP3 — are important components of a multi-protein DNA-binding complex that helps direct differentiation of red blood cell precursors. Specifically, SSBP2 increased levels of two other key proteins in this complex (Ldb1 and Lmo2) by protecting them from degradation.

In addition to this novel role in cellular differentiation, the findings suggest that, since several cancer types show abnormal expression of SSBPs, altered expression of SSBPs may contribute to tumorigenesis by disrupting the normal balance of these DNA-binding complexes.

— Melissa Marino

Lungs’ lining plays role in injury

We rely on the epithelial cell lining in our lungs to provide a protective physical border that “sweeps away” the infectious and harmful agents we inhale. Timothy Blackwell, M.D., and colleagues are probing whether the airway epithelium also plays roles in the innate immune response and development of lung injury.

The investigators generated a transgenic mouse system to modulate the activity of the transcription factor NF-kappa-B, a known mediator of inflammatory processes, in specific cell types. They report in the May 15 Journal of Immunology that activation of NF-kappa-B in the mouse airway epithelium resulted in inflammation, progressive lung injury and death. Inhibition of NF-kappa-B activity prevented lung inflammation and injury in response to the E. coli endotoxin LPS. The findings implicate the NF-kappa-B pathway in airway epithelial cells in the generation of lung inflammation and injury, suggesting these cells may be an important target for reducing or preventing lung injury in critically ill patients.

— Leigh MacMillan

Past Aliquots

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