Biomedical subjects

Michael Cornell

Publications and source records attributed to Michael Cornell.

4 recordsLinked to original sources

PubMed2004

Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins.

The Notch receptor mediates a short-range signal that regulates many cell fate decisions. The misregulation of Notch has been linked to cancer and to developmental disorders. Upon binding to its ligands, Delta (Dl) or Serrate (Ser), the Notch ectodomain is shed by the action of an ADAM protease. The Notch intracellular domain is subsequently released proteolytically from the membrane by Presenilin and translocates to the nucleus to activate the transcription factor, Suppressor of Hairless. We show in Drosophila that Notch signaling is limited by the activity of two Nedd4 family HECT domain proteins, Suppressor of deltex [Su(dx)] and DNedd4. We rule out models by which Su(dx) downregulates Notch through modulating Deltex or by limiting the adherens junction accumulation of Notch. Instead, we show that Su(dx) regulates the postendocytic sorting of Notch within the early endosome to an Hrs- and ubiquitin-enriched subdomain en route to the late endosome. We propose a model in which endocytic sorting of Notch mediates a decision between its activation and downregulation. Such intersections between trafficking routes may provide key points at which other signals can modulate Notch activity in both normal development and in the pathological misactivation of Notch.

Animals↗

PubMed2003

Down-regulation of Notch target gene expression by Suppressor of deltex.

In Drosophila, Suppressor of deltex (Su(dx)) mutations display a wing vein gap phenotype resembling that of Notch gain of function alleles. The Su(dx) protein may therefore act as a negative regulator of Notch but its activity on actual Notch signalling levels has not been demonstrated. Here we show that Su(dx) does regulate the level of Notch signalling in vivo, upstream of Notch target genes and in different developmental contexts, including a previously unknown role in leg joint formation. Overexpression of Su(dx) was capable of blocking both the endogenous activity of Notch and the ectopic Notch signalling induced by the overexpression of Deltex, an intracellular Notch binding protein. In addition, using the conditional phenotype of the Su(dx)(sp) allele, we show that loss of Su(dx) activity is rapidly followed by an up-regulation of E(spl)mbeta expression, the immediate target of Notch signal activation during wing vein development. While Su(dx) adult wing vein phenotypes are quite mild, only affecting the distal tips of the veins, we show that the initial consequence of loss of Su(dx) activity is more severe than previously thought. Using a time-course experiment we show that the phenotype is buffered by feedback regulation illustrating how signalling networks can make development robust to perturbation.

Alleles↗

PubMed2003

GIMS: an integrated data storage and analysis environment for genomic and functional data.

Effective analyses in functional genomics require access to many kinds of biological data. For example, the analysis of upregulated genes in a microarray experiment might be aided by information concerning protein interactions or proteins' cellular locations. However, such information is often stored in different formats at different sites, in ways that may not be amenable to integrated analysis. The Genome Information Management System (GIMS) is an object database that integrates genomic data with data on the transcriptome, protein-protein interactions, metabolic pathways and annotations, such as gene ontology terms and identifiers. The resulting system supports the running of analyses over this integrated data resource, and provides comprehensive facilities for handling and interrelating the results of these analyses. GIMS has been used to store Saccharomyces cerevisiae data, and we demonstrate how the integrated storage of diverse types of data can be beneficial for analysis, using combinations of complex queries. As an example, we describe how GIMS has been used to analyse a collection of aryl alcohol dehydrogenase gene deletion mutants. The GIMS database can be accessed remotely using a Java application that can be downloaded from http://img.cs.man.ac.uk/gims.

Computational Biology↗

PubMed2002

Comparative assessment of large-scale data sets of protein-protein interactions.

Comprehensive protein protein interaction maps promise to reveal many aspects of the complex regulatory network underlying cellular function. Recently, large-scale approaches have predicted many new protein interactions in yeast. To measure their accuracy and potential as well as to identify biases, strengths and weaknesses, we compare the methods with each other and with a reference set of previously reported protein interactions.

Bias↗