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Characterization of inhibitors of glucocorticoid receptor nuclear translocation: a model of cytoplasmic dynein-mediated cargo transport. | LitMetric

AI Article Synopsis

  • * Evaluated the effects of these compounds on cell structure and toxicity through imaging techniques, highlighting the complexity of the transport process and potential targets for disruption.
  • * Found that while some compounds showed strong activity against dynein and other proteins involved in transport, many lacked specificity, suggesting a need for more targeted inhibitors to effectively study retrograde transport mechanisms.

Article Abstract

Agonist-induced glucocorticoid receptor [GR] transport from the cytoplasm to the nucleus was used as a model to identify dynein-mediated cargo transport inhibitors. Cell-based screening of the library of pharmacologically active compound (LOPAC)-1280 collection identified several small molecules that stalled the agonist-induced transport of GR-green fluorescent protein (GFP) in a concentration-dependent manner. Fluorescent images of microtubule organization, nuclear DNA staining, expression of GR-GFP, and its subcellular distribution were inspected and quantified by image analysis to evaluate the impact of compounds on cell morphology, toxicity, and GR transport. Given the complexity of the multi-protein complex involved in dynein-mediated cargo transport and the variety of potential mechanisms for interruption of that process, we therefore developed and validated a panel of biochemical assays to investigate some of the more likely intracellular target(s) of the GR transport inhibitors. Although the apomorphine enantiomers exhibited the most potency toward the ATPase activities of cytoplasmic dynein, myosin, and the heat-shock proteins (HSPs), their apparent lack of specificity made them unattractive for further study in our quest. Other molecules appeared to be nonspecific inhibitors that targeted reactive cysteines of proteins. Ideally, specific retrograde transport inhibitors would either target dynein itself or one of the other important proteins associated with the transport process. Although the hits from the cell-based screen of the LOPAC-1280 collection did not exhibit this desired profile, this screening platform provided a promising phenotypic system for the discovery of dynein/HSP modulators.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277738PMC
http://dx.doi.org/10.1089/adt.2010.0367DOI Listing

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