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Intramural Papers of the Month

By Robin Arnette
January 2009

Anti-Hu is a Possible Marker for Small Cell Lung Cancer

Antibodies against Hu proteins (anti-Hu) are a potential marker for small cell lung cancer (SCLC) according to a team of scientists from NIEHS, the University of Southern California and the University of California Los Angeles. Since SCLC is one of the fastest and deadliest cancers, finding this marker could improve survival in SCLC patients.

Hu proteins, a family of RNA-binding proteins, are homologous to the embryonic lethal abnormal visual (ELAV) protein in Drosophila and are involved in neuron-specific RNA processing and neural development. Previous studies from other labs had determined that SCLC tumors express Hu proteins and that anti-Hu reactivity occurred in 17—25.5 percent of SCLC patients.

To find out whether anti-Hu antibodies were associated with an increased risk of developing SCLC, the investigators analyzed levels of anti-Hu antibodies in 41 SCLC patients and 79 matched population controls. The team used recombinant HuD protein, one of the four Hu proteins, in a Western blot analysis and determined that 15 percent of SCLC patients had detectable anti-Hu activity.

The research is the first report of a correlation between anti-Hu reactivity and SCLC in a population-based study, but the authors point out that large-scale studies are needed to determine if anti-Hu profiles can be used as a SCLC detection marker.

Tsou JA, Kazarian M, Patel A, Galler JS, Laird-Offringa IA, Carpenter CL, London SJ. 2009. ( Exit NIEHS Low level anti-Hu reactivity: A risk marker for small cell lung cancer? Cancer Detect Prev 32(4):292-299.

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Environmental and Genetic Factors Are Basis of Disease

Using several databases and analysis algorithms, scientists from NIEHS, the National Institute on Aging and the Mount Desert Island Biological Laboratory have identified significant molecular pathways that link human disease with environmental factors and genetics. The authors argue that knowledge-based, systems-driven evaluations like the one presented in the publication, will improve public health by offering promising areas of research.

The research team used Structurally Enhanced Pathway Enrichment Analysis (SEPEA) to analyze gene-phenotype relationships found in the Genetic Association Database (GAD). The investigators also studied how environmental and genetic susceptibility factors contribute to a specific phenotype, by identifying pathways of environmental factor-gene protein relationships in the Comparative Toxicogenomics Database. The result was an interactome describing the relationships between human disease and environmental exposure mediated through metabolic and signal-transduction pathways.

The evaluation resulted in several clusters, such as immune related pathways (e.g. Toll-like receptor signaling) resulting in autoimmune diseases as well as cardiovascular, kidney and Alzheimer's disease. The work identified seemingly unrelated clusters (e.g. neuropsychiatric disorders, obesity and lung disease) that create hypotheses for future research.

Gohlke JM, Thomas R, Zhang Y, Rosenstein MC, Davis AP, Murphy C, Becker KG, Mattingly CJ, Portier CJ.( Exit NIEHS 2009. Genetic and environmental pathways to complex diseases. BMC Syst Biol 3:46; doi: 10.1186/1752-0509-3-46 [online 5 May 2009].

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Hyaluronan Contributes to Murine Airway Hyperresponsiveness

Researchers from NIEHS, Duke University, Aichi Medical University in Japan, the University of Texas Southwestern Medical Center and the National Jewish Medical and Research Center have discovered that hyaluronan, an abundant extracellular matrix component, mediates ozone-induced airway hyperreactivity (AHR). The work sheds more light on the pathogenesis of environmental airway disease and is the first study to show that short fragments of hyaluronan contribute to AHR following ozone exposure.

The collaborative team found that mice exposed to ozone had high levels of hyaluronan in lung lavage fluid and exhibited AHR. Mice that were deficient in CD44, a hyaluronan receptor, and inter-α-trypsin inhibitor (IaI), a molecule that facilitates hyaluronan binding, also had elevated levels of hyaluronan in the lavage fluid, but were protected from ozone-induced AHR.

The size of the hyaluronan fragment instilled into the lung was also found to determine whether AHR occurred after ozone exposure — low molecular weight hyaluronan induced AHR after ozone, while high molecular weight hyaluronan protected against the disorder. These data have identified hyaluronan as a potential target for the treatment of AHR.

Garantziotis S, Li Z, Potts EN, Kimata K, Zhuo L, Morgan DL, Savani RC, Noble PW, Foster WM, Schwartz DA, Hollingsworth JW.( Exit NIEHS 2009. Hyaluronan mediates ozone-induced airway hyperresponsiveness in mice. J Biol Chem 284(17): 11309-11317.

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Development of Polycystic Kidney Disease and Type I Diabetes in Glis3-Deficent Mice

Glis3 is a member of a subfamily of Krüppel-like zinc finger transcription regulators previously identified by the Jetten lab at NIEHS. The researchers generated mutant mice (Glis3zf/zf) that were deficient in Glis3, and the mice exhibited characteristics similar to those observed in patients with the disorder "neonatal diabetes and congenital hypothyroidism" (NDH). As in NDH patients, these mutant mice had a short life span and developed Type I diabetes and polycystic kidney disease (PKD).

Studies from other labs found a link between proteins involved in cystic renal diseases and signaling pathways associated with the primary cilium, a sensory organelle that is part of most cells. The concept was substantiated in this study when Glis3 was found to be associated with the primary cilium in renal tubules, suggesting that Glis3 is part of a primary cilium signaling pathway.

In addition, the team found the connection between Glis3 and the transcriptional modulator Wwtr1. Both Glis3zf/zf and Wwtr1 null mice developed glomerulocysts. Co-immunoprecipitation and mammalian two-hybrid analyses confirmed that Glis3 and Wwtr1 were part of the same complex. Pull-down and point mutation analysis demonstrated that Glis3 directly interacts with Wwtr1. The investigators subsequently demonstrated that Wwtr1 functioned as a coactivator of Glis3-mediated transcription.

Kang HS, Beak JY, Kim YS, Herbert R, Jetten AM.( Exit NIEHS 2009. Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease. Mol Cell Biol 29(10):2556-2569.

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