Project description:DHPM-thiones rescue Ab-mediated toxicity in a metal-dependent manner that strongly synergizes with clioquinol, a known metal-binding and cytoprotective compound. RNA-seq experiments reveal a modest, yet specific effect on metal-responsive genes that do not change with the inactive control compound.
Project description:Cr(VI) is a common bioavailable toxic metal that can cause oxidative stress, DNA adducts, and perturb normal gene expression. Changes in gene expression are useful biomarkers of toxicant exposure that provide information about the health of an organism, its ability to adapt to its environment, and indicate potential toxicant-specific effects. Therefore, we developed a toxicology array to the estuarine sentinel species Fundulus heteroclitus, or mummichog. Adults males were exposed to Cr(VI) for 7-days at 0, 1.5 (NOEC), or 3 mg/L (LOEC). Livers were excised and RNA isolated. Adults are used in the laboratory experiments so that we can compare laboratory studies to fish caught at chromium-contaminated field sites. Cr(VI) altered the expression of 12 genes in adult liver, including hepatic growth factor activator, heart fatty acid binding protein, and complement component C3-2. Keywords: dose response
Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Nestin+ and Nestin- GNPs (granule neuron precursors) were purified from Nestin-CFP/Math1-Cre/Ptch1-loxp cerebella at postnatal day 4 by FACs, and total RNA from these two cell populations were extracted, and then labeled and hybridized to Affymetrix Mouse Genome 430 2.0 arrays.