15 research outputs found

    Detection of changes in gene regulatory patterns, elicited by perturbations of the Hsp90 molecular chaperone complex, by visualizing multiple experiments with an animation

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental conditions, and the proteins encoded by these genes interact and function in the same cellular compartments, this could be taken as very strong indicators for co-regulated protein complexes. One of the key requirements is having appropriate tools to detect such regulatory patterns.</p> <p>Results</p> <p>We have analyzed the global adaptations in gene expression patterns in the budding yeast when the Hsp90 molecular chaperone complex is perturbed either pharmacologically or genetically. We integrated these results with publicly accessible expression, protein-protein interaction and intracellular localization data. But most importantly, all experimental conditions were simultaneously and dynamically visualized with an animation. This critically facilitated the detection of patterns of gene expression changes that suggested underlying regulatory networks that a standard analysis by pairwise comparison and clustering could not have revealed.</p> <p>Conclusions</p> <p>The results of the animation-assisted detection of changes in gene regulatory patterns make predictions about the potential roles of Hsp90 and its co-chaperone p23 in regulating whole sets of genes. The simultaneous dynamic visualization of microarray experiments, represented in networks built by integrating one's own experimental with publicly accessible data, represents a powerful discovery tool that allows the generation of new interpretations and hypotheses.</p

    Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction.

    No full text
    Raw data for &#39;Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction.&#39; The dataset contains the raw data used to generate the figures in the above manuscript. Each data file is labelled with the corresponding figure number used in the manuscript. The files were generated with Graphpad Prism 7. The folder contains the following files: * data used in Figure 1B * data used in Figure 2A-2C * data used in Figure 2D * data used in Figure 2E * data used in Figure 3 * data used in Figure 4A-4K * data used in Figure 5C If you require additional information please contact the corresponding author of the manuscript.</span

    Fungi and animals may share a common ancestor to nuclear receptors

    No full text
    Nuclear receptors (NRs) are a large family of transcription factors. One hallmark of this family is the ligand-binding domain (LBD), for its primary sequence, structure, and regulatory function. To date, NRs have been found exclusively in animals and sponges, which has led to the generally accepted notion that they arose with them. We have overcome the limitations of primary sequence searches by combining sequence profile searches with structural predictions at a genomic scale, and have discovered that the heterodimeric transcription factors Oaf1/Pip2 of the budding yeast Saccharomyces cerevisiae contain putative LBDs resembling those of animal NRs. Although the Oaf1/Pip2 LBDs are embedded in an entirely different architecture, the regulation and function of these transcription factors are strikingly similar to those of the mammalian NR heterodimer peroxisome proliferator-activated receptor α/retinoid X receptor (PPARα/RXR). We demonstrate that the induction of Oaf1/Pip2 activity by the fatty acid oleate depends on oleate’s direct binding to the Oaf1 LBD. The alteration of two amino acids in the predicted ligand-binding pocket of Oaf1 abolishes both ligand binding and the transcriptional response. Hence, LBDs may have arisen as allosteric switches, for example, to respond to nutritional and metabolic ligands, before the animal and fungal lineages diverged

    HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature

    No full text
    publisher versionThe Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation
    corecore