Synthetic Molecule Turns Off Asthma-Invoking Protein; Get the Lead Out -- It Kills the Mitochondria; Interdisciplinary Research

Courtesy of Michael Kahn Synthetic Molecule Turns Off Asthma-Invoking Protein Asthma's trademark is a complex inflammatory response in the lungs that produces swelling and mucus, therefore making it difficult to breathe. One of the main components of this disease is an oxidant/antioxidant imbalance that can trigger production of activator protein-1 (AP-1). Researchers have designed a novel synthetic molecule with the power to target and turn-off this asthma-invoking protein (C. Nguyen et al., "Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma," Proc Natl Acad Sci, 100:1169-73, 2003). Using a chemogenomics approach, pathobiologist Michael Kahn and his colleagues at the Pacific Northwest Research Institute (PNRI) in Seattle developed a number of potential small- molecule inhibitors of AP-1 transcription. Once investigators identified molecular PNRI-299 as the best candidate, they tested it in murine asthma models. In their study, PNRI-299 decreased airway swelling and mucus production. "PNRI inhibits AP-1 transcription of inflammatory genes, such as IL-4, which are key players in asthma," says Kahn. The finding could lead to better therapies for asthma and airway fibrosis. For example, Kahn believes a PNRI compound could be used as the backbone for an aerosol-based asthma medication. One of the shortcomings of PNRI-299, however, is its short half-life in vivo. Kahn's team is currently working on longer-lasting templates. --Kelli Miller Courtesy of Donald Fox Get the Lead Out -- It Kills the Mitochondria Neurotoxicologist Donald Fox and colleagues, who study the effects of prenatal lead exposure in children, have developed a murine model to help explain how neurons gets damaged and to explain how postnatal exposure affects children (L. He et al., "Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice," Proc Nat Acad Sci, 100:1022-7, Feb. 4, 2003). "The early prenatal exposure to lead caused these kids to have a retinal deficit up to 10 years later," says Fox, who is from the University of Houston. Because it's difficult to study effects of early postnatal lead exposure in children, the researchers developed a transgenic model overexpressing Bcl-xL; this gene hampers lead's cellular processes. They specifically studied lead's effect on retinal cells as an accessible example of neurological effects. In control mice, Fox's group found small amounts of lead, which causes the proapoptotic protein Bax to translocate from the cell's cytosol to the mitochondria. Lead also increases calcium ions in rod cells, resulting in increased contact sites in the mitochondrial membrane and decreased mitochondrial membrane potential. The mitochondrial effects trigger a release of cytochrome c, setting in motion cellular apoptosis. The mice are protected by the gene Bcl-xL, which renders murine cells insensitive to calcium ion overload; the cells therefore do not undergo apoptosis. Rods in the lead-exposed transgenic mice are rescued, and they continue functioning normally. Fox says that this research may result in "some pharmacological agents to prevent some of the poisoning that the lead agent produces." --Myrna E. Watanabe Interdisciplinary Research These papers were selected from multiple disciplines from the Faculty of 1000, a Web-based literary awareness tool (www.facultyof1000.com). T.I. Lee et al., "Transcriptional regulatory networks in Saccharomyces cerevisiae," Science, 298:799-804, Oct. 25, 2002. "This paper represents a major attempt to study regulatory networks in yeast through protein-gene binding studies and RNA expression analysis ... a breakthrough paper with methods and results that should get used also in other areas of eukaryote research!" --Oliver Fiehn, Max Planck Institute of Molecular Plant Physiology S. Etienne-Manneville et al., "Cdc42 regulates GSK-3ß and adenomatous polyposis coli to control cell polarity," Nature, 421:753-6, Feb. 13, 2003. "A fascinating study that elegantly connects and coordinates two of the major biochemical systems involved in cell polarity and cell migration." --Christopher A. Walsh, Harvard University W. Winkler et al., "Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression," Nature, 419:952-6, Oct. 31, 2002. "The significance of these findings is that they further expand the burgeoning recognition of the role of nucleic acids in gene regulation, not as mere sites for the touchdown of proteins, but as important machines in their own right (e.g., siRNA and micro RNAs)." --Andrew Ellington, University of Texas, Austin G.H. Patterson et al., "A photoactivatable GFP for selective photolabeling of proteins and cells," Science, 297:1873-7, Sept. 13, 2002. "The discovery of a mutant form of the green fluorescent protein (GFP) that is photoactivatable ... is a significant technical advance. This exciting molecular tool is likely to be of great importance for studying the spatial and temporal dynamics of protein trafficking in any type of cell." --A. Kimberly McAllister, University of California, Davis

Synthetic Molecule Turns Off Asthma-Invoking Protein; Get the Lead Out -- It Kills the Mitochondria; Interdisciplinary Research

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