Biomedical subjects

Jason D Oliver

Publications and source records attributed to Jason D Oliver.

4 recordsLinked to original sources

PubMed2005

Gene ontology mapping as an unbiased method for identifying molecular pathways and processes affected by toxicant exposure: application to acute effects caused by the rodent non-genotoxic carcinogen diethylhexylphthalate.

Toxicogenomics has the potential to reveal the molecular pathways and cellular processes that mediate the adverse responses to a toxicant. However, the initial output of a toxicogenomic experiment often consists of large lists of genes whose expression is altered after toxicant exposure. To interpret gene expression changes in the context of underlying biological pathways and processes, new bioinformatics methods must be developed. We have used global gene expression profiling combined with an evaluation of Gene Ontology (GO) and pathway mapping tools as unbiased methods for identifying the molecular pathways and processes affected upon toxicant exposure. We chose to use the acute effects caused by the non-genotoxic carcinogen and peroxisome proliferator (PP) diethylhexylphthalate (DEHP) in the mouse liver as a model system. Consistent with what is known about the mode of action of DEHP, our GO analysis of transcript profiling data revealed a striking overrepresentation of genes associated with the peroxisomal cellular component, together with genes involved in carboxylic acid and lipid metabolism. Furthermore we reveal gene expression changes associated with additional biological functions, including complement activation, hemostasis, the endoplasmic reticulum overload response, and circadian rhythm. Together, these data reveal potential new pathways of PP action and shed new light on the mechanisms by which non-genotoxic carcinogens control hepatocyte hypertrophy and proliferation. We demonstrate that GO mapping can identify, in an unbiased manner, both known and novel DEHP-induced molecular changes in the mouse liver and is therefore a powerful approach for elucidating modes of toxicity based on toxicogenomic data.

Animals↗

PubMed2004

The primary substrate binding site in the b' domain of ERp57 is adapted for endoplasmic reticulum lectin association.

ERp57 is a member of the protein disulfide isomerase (PDI) family that is located in the endoplasmic reticulum (ER) and characterized by its specificity for glycoproteins. Substrate selection by ERp57 is dependent upon its formation of discrete complexes with two ER resident lectins, soluble calreticulin and membrane-bound calnexin. It is these two lectins that directly associate with glycoproteins bearing correctly trimmed oligosaccharide side chains. Thus, ERp57 is presented with a preselected set of substrates upon which it can act, and the specific binding of calreticulin and calnexin to ERp57 is pivotal to the functions of the resulting complexes. To gain further insights into the formation of these ERp57-ER lectin complexes, we have investigated the regions of ERp57 that are specifically required for its binding to calreticulin. Using a quantitative pull-down assay to investigate the binding of ERp57/PDI chimeras to calreticulin, we define the b and b' domains of ERp57 as the minimal elements that are sufficient for complex formation. This analysis further identifies a novel role for the distinctive C-terminal extension of ERp57 in reconstituting complex formation to wild type levels. Using our understanding of substrate binding to the b' domain of PDI as a paradigm, we show that alterations to specific residues in the b' domain of ERp57 dramatically reduce or completely abolish its binding to calreticulin. On the basis of these data, we propose a model where the region of ERp57 equivalent to the primary substrate binding site of archetypal PDI is occupied by calreticulin and suggest that the ER lectins act as adaptor molecules that define the substrate specificity of ERp57.

Amino Acid Sequence↗

PubMed2002

Tail-anchored and signal-anchored proteins utilize overlapping pathways during membrane insertion.

Tail-anchored proteins are a distinct class of membrane proteins that are characterized by a C-terminal membrane insertion sequence and a capacity for post-translational integration. Although it is now clear that tail-anchored proteins are inserted into the membrane at the endoplasmic reticulum (ER), the molecular basis for their integration is poorly understood. We have used a cross-linking approach to identify ER components that may be involved in the membrane insertion of tail-anchored proteins. We find that several newly synthesized tail-anchored proteins are transiently associated with a defined subset of cellular components. Among these, we identify several ER proteins, including subunits of the Sec61 translocon, Sec62p, Sec63p, and the 25-kDa subunit of the signal peptidase complex. When we analyze the cotranslational membrane insertion of a comparable signal-anchored protein we find the nascent polypeptide associated with a similar set of ER components. We conclude that the pathways for the integration of tail-anchored and signal-anchored membrane proteins at the ER exhibit a substantial degree of overlap, and we propose that this reflects similarities between co- and post-translational membrane insertion.

Cell Membrane↗

PubMed2002

Receptor-mediated hepatocarcinogenesis: role of hepatocyte proliferation and apoptosis.

The rodent liver is a target organ for the action of several non-genotoxic carcinogens. These include dioxins, polychlorinated biphenyls, phenobarbital, peroxisome proliferators and organochlorine pesticides. These chemicals disrupt the homeostasis of the liver by perturbing hepatocyte cell death and proliferation, causing hyperplasia leading to tumour formation. Significant progress has been made towards elucidating the mechanisms of action of these toxicants since the discovery of receptors that bind specific classes of xenobiotics. Dioxins and polychlorinated biphenyls bind to the aryl hydrocarbon receptor, phenobarbital binds to the constitutive androstane receptor and peroxisome proliferators act via the their activated receptor alpha. These three receptors have ligand-dependent transcription activities and therefore mediate changes in gene expression in response to toxicant exposure. The development of transgenic mouse strains where the genes for these receptors are disrupted has demonstrated that receptor activity is essential for the toxicity of these carcinogens. This implies that changes in the expression of key target genes control proliferation and apoptosis in the xenobiotic-induced hepatocyte phenotype.

Animals↗