Biomedical subjects

Timothy R Hughes

Publications and source records attributed to Timothy R Hughes.

59 records · Page 4Linked to original sources

PubMed2002

FunSpec: a web-based cluster interpreter for yeast.

BACKGROUND: For effective exposition of biological information, especially with regard to analysis of large-scale data types, researchers need immediate access to multiple categorical knowledge bases and need summary information presented to them on collections of genes, as opposed to the typical one gene at a time. RESULTS: We present here a web-based tool (FunSpec) for statistical evaluation of groups of genes and proteins (e.g. co-regulated genes, protein complexes, genetic interactors) with respect to existing annotations (e.g. functional roles, biochemical properties, localization). FunSpec is available online at http://funspec.med.utoronto.ca CONCLUSION: FunSpec is helpful for interpretation of any data type that generates groups of related genes and proteins, such as gene expression clustering and protein complexes, and is useful for predictive methods employing "guilt-by-association."

Cluster Analysis↗

PubMed2002

Large-scale prediction of Saccharomyces cerevisiae gene function using overlapping transcriptional clusters.

Genome sequencing has led to the discovery of tens of thousands of potential new genes. Six years after the sequencing of the well-studied yeast Saccharomyces cerevisiae and the discovery that its genome encodes approximately 6,000 predicted proteins, more than 2,000 have not yet been characterized experimentally, and determining their functions seems far from a trivial task. One crucial constraint is the generation of useful hypotheses about protein function. Using a new approach to interpret microarray data, we assign likely cellular functions with confidence values to these new yeast proteins. We perform extensive genome-wide validations of our predictions and offer visualization methods for exploration of the large numbers of functional predictions. We identify potential new members of many existing functional categories including 285 candidate proteins involved in transcription, processing and transport of non-coding RNA molecules. We present experimental validation confirming the involvement of several of these proteins in ribosomal RNA processing. Our methodology can be applied to a variety of genomics data types and organisms.

Algorithms↗

PubMed2002

Yeast and drug discovery.

Advanced genetic techniques, along with the high degree of conservation of basic cellular processes, have made the yeast Saccharomyces cerevisiae a valuable system for identification of new drug targets, target-based and non-target-based drug screening, and detailed analysis of the cellular effects of drugs. Yeast also presents a convenient system for antifungal drug discovery because it is closely related to Candida albicans, a major human pathogen. Many yeast genes remain poorly characterized, and most of the sophisticated techniques in yeast have been in widespread use less than a decade - a period shorter than the typical cycle from target identification to marketing approval for a new drug. It is likely that most of the benefits of yeast in discovery and development of therapeutic compounds have yet to be realized.

Antifungal Agents↗

PubMed2002

Conserved structure for single-stranded telomeric DNA recognition.

The essential Cdc13 protein in the yeast Saccharomyces cerevisiae is a single-stranded telomeric DNA binding protein required for chromosome end protection and telomere replication. Here we report the solution structure of the Cdc13 DNA binding domain in complex with telomeric DNA. The structure reveals the use of a single OB (oligonucleotide/oligosaccharide binding) fold augmented by an unusually large loop for DNA recognition. This OB fold is structurally similar to OB folds found in the ciliated protozoan telomere end-binding protein, although no sequence similarity is apparent between them. The common usage of an OB fold for telomeric DNA interaction demonstrates conservation of end-protection mechanisms among eukaryotes.

Binding Sites↗

PubMed2002

A novel role of Sp1 and Sp3 in the interferon-gamma -mediated suppression of macrophage lipoprotein lipase gene transcription.

The regulation of macrophage lipoprotein lipase by cytokines is of potentially crucial importance in the pathogenesis of atherosclerosis. We have shown previously that macrophage lipoprotein lipase expression is suppressed by interferon-gamma (IFN-gamma) at the transcriptional level. We investigated the regulatory sequence elements and the transcription factors that are involved in this response. We demonstrated that the -31/+187 sequence contains the minimal IFN-gamma-responsive elements. Electrophoretic mobility shift assays showed that the binding of proteins to two regions in the -31/+187 sequence was reduced dramatically when the cells were exposed to IFN-gamma. Both competition electrophoretic mobility shift assays and antibody supershift assays showed that the interacting proteins were composed of Sp1 and Sp3. Mutations of the Sp1/Sp3-binding sites in the minimal IFN-gamma-responsive elements abolished the IFN-gamma-mediated suppression of promoter activity, whereas multimers of the sequence were able to impart the response to a heterologous promoter. Western blot analysis showed that IFN-gamma reduced the steady state levels of Sp3 protein. In contrast, the cytokine decreased the DNA binding activity of Sp1 without affecting the protein levels. These studies therefore reveal a novel mechanism for IFN-gamma-mediated regulation of macrophage gene transcription.

Base Sequence↗