A5082257089- Cancer, Hypoxia, and Metabolism
- Toxic Organic Pollutants Impact
- Adipose Tissue and Metabolism
- Epigenetics and DNA Methylation
- Carcinogens and Genotoxicity Assessment
- Heat shock proteins research
- Mitochondrial Function and Pathology
- High Altitude and Hypoxia
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- Mass Spectrometry Techniques and Applications
- RNA Research and Splicing
- Environmental Toxicology and Ecotoxicology
- Effects and risks of endocrine disrupting chemicals
- RNA modifications and cancer
- Pluripotent Stem Cells Research
- Single-cell and spatial transcriptomics
- Glutathione Transferases and Polymorphisms
- Estrogen and related hormone effects
- Pancreatic function and diabetes
- Congenital heart defects research
- Computational Drug Discovery Methods
- Biotin and Related Studies
- Genomics and Rare Diseases
- bioluminescence and chemiluminescence research
The University of Adelaide
2015-2025
National Neuroscience Institute
2023-2025
The University of Melbourne
2020
Austin Health
2020
Peninsula Health
2020
Eastern Health
2016-2020
Monash Health
2016-2020
Monash University
2012-2020
University of Glasgow
2016-2020
Australian Catholic University
2020
The hypoxia-inducible factors (HIFs) 1alpha and 2alpha are key mammalian transcription that exhibit dramatic increases in both protein stability intrinsic transcriptional potency during low-oxygen stress. This increased is due to the absence of proline hydroxylation, which normoxia promotes binding HIF von Hippel-Lindau (VHL tumor suppressor) ubiquitin ligase. We now show hypoxic induction COOH-terminal transactivation domain (CAD) occurs through abrogation hydroxylation a conserved...
Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by the hypoxia-inducible factor, HIF. HIF activity is suppressed under normoxic hydroxylation of an asparagine residue within its C-terminal transactivation domain, blocking association with coactivators. Here we show that protein FIH-1, previously shown interact HIF, asparaginyl hydroxylase. Like known hydroxylase enzymes, FIH-1 Fe(II)-dependent enzyme uses molecular O 2 modify substrate....
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and the intracellular dioxin receptor mediate hypoxia signalling, respectively. Both proteins are conditionally regulated basic helix-loop-helix (bHLH) transcription factors that, in addition to bHLH motif, share a Per-Arnt-Sim (PAS) region of homology form heterodimeric complexes with common bHLH/PAS partner Arnt. Here we demonstrate that HIF-1 required Arnt for DNA binding vitro functional activity vivo. PAS motifs were critical dimerization...
The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating of battery genes encoding xenobiotic metabolizing enzymes. Known ligands are environmental pollutants including polycyclic aromatic hydrocarbons and polychlorinated dioxins. Loss-of-function (gene-disruption) studies in mice have demonstrated that the AhR is involved toxic effects dioxins but not yielded unequivocal results concerning physiological function receptor. Gain-of-function...
Cells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1alpha (HIF-1alpha) becomes stabilized and directly activates transcription of downstream genes. In addition this "canonical" certain aspects the pathway require integration with Notch signaling, i.e., HIF-1alpha can interact intracellular domain (ICD) augment response. work, we demonstrate an additional level complexity in cross-talk: factor-inhibiting HIF-1 (FIH-1) regulates not only HIF activity, but also...
The hypoxia-inducible factor (HIF)-1α and HIF-2α are closely related, key transcriptional regulators of the hypoxic response, countering a low oxygen situation with up-regulation target genes associated numerous processes, including vascularization glycolysis. This involves dual mechanism control through both stabilization transactivation, regulated via prolyl asparaginyl hydroxylation. Despite high similarity respect to protein sequence activation pathway, growing number physiological...
The intracellular basic region/helix-loop-helix (bHLH) dioxin receptor mediates signal transduction by (2,3,7,8-tetrachlorodibenzo-p-dioxin) and functions as a ligand-activated DNA binding protein directly interacting with target genes to response elements. Here we show that the partially purified, ligand-bound alone could not bind DNA. In contrast, be induced addition of cytosolic auxiliary activity which functionally biochemically corresponded bHLH factor Arnt. While Arnt exhibited no...
Monoclonal antibody (mAb) 8D3 and 3G3 are unique antibodies capable of precipitating both free 90-kDa heat shock protein (HSP90) HSP90-protein complexes. Immunoprecipitation [35S]methionine-labeled Hepa 1c1c7 cytosolic extracts were performed using mAb or 3G3. The resulting immunoprecipitates can be dissociated from the with a 500 mM NaCl wash. These washes subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis two-dimensional electrophoresis. Five major spots detected in...
Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of paraventricular nucleus hypothalamus. Obesity has been reported Sim1 haploinsufficient mice patient with balanced translocation disrupting SIM1. We sequenced coding region SIM1 2,100 patients severe, early onset obesity 1,680 controls. Thirteen different heterozygous variants were identified 28 unrelated severely obese patients. Nine 13 significantly reduced ability to activate...
Background Without appropriate cellular models the etiology of idiopathic Parkinson's disease remains unknown. We recently reported a novel patient-derived model generated from biopsies olfactory mucosa (termed neurosphere-derived (hONS) cells) which express functional and genetic differences in disease-specific manner. Transcriptomic analysis Patient Control hONS cells identified NRF2 transcription factor signalling pathway as most differentially expressed disease. Results tested robustness...
Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, chromosome 6q16, a region that includes SIM1, were reported obese children with Prader-Willi-like syndrome; however, SIM1 involvement has never been conclusively demonstrated. Here, was sequenced 44 syndrome features, 198 severe early-onset obesity, 568 morbidly adults, 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, p.T714A) features (including...
Hypoxia-inducible factor 1α (HIF-1α) and the HIF-like (HLF) are two highly related basic Helix-Loop-Helix/Per-Arnt-Sim (bHLH/PAS) homology transcription factors that undergo dramatically increased function at low oxygen levels. Despite strong similarities in their activation mechanisms (<i>e.g.</i> they both rapid hypoxia-induced protein stabilization, bind identical target DNA sequences, induce synthetic reporter genes to similar degrees), essential for embryo survival via distinct...
The dioxin receptor is a cytoplasmic basic helix-loop-helix/Per-Arnt-Sim homology (bHLH/PAS) protein known to bind planar polycyclic ligands including aromatic hydrocarbons, benzoflavones, heterocyclic amines, and halogenated e.g. dioxins. Ligand-induced activation of the initiates process whereby transformed into nuclear transcription factor complex with specific bHLH/PAS partner protein, Arnt. In analogy glucocorticoid receptor, latent found associated molecular chaperone hsp90. We have...
Gene regulation by dioxins is mediated via the dioxin receptor, a ligand-dependent basic helix-loop-helix (bHLH)/PAS transcription factor. The latent receptor responds to signalling forming an activated heterodimeric complex with specific bHLH partner, Arnt, essential process for target DNA recognition. We have analyzed transactivating potential within this dissecting it into individual subunits, replacing dimerization and DNA-binding motifs heterologous zinc finger domains. uncoupled Arnt...
Signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) is mediated the intracellular receptor which, in its dioxin-activated state, regulates transcription of target genes encoding drug-metabolizing enzymes, such as cytochrome P-450IA1 and glutathione S-transferase Ya. Exposure to leads an apparent translocation nucleus vivo a rapid conversion from latent, non-DNA-binding form species that binds dioxin-responsive positive control elements vitro. This DNA-binding appears be...
In response to dioxin, the nuclear basic helix-loop-helix (bHLH) dioxin receptor forms a complex with bHLH partner factor Arnt that regulates target gene transcription by binding dioxin-responsive sequence motifs. Previously, we have demonstrated latent form of present in extracts from untreated cells is stably associated molecular chaperone protein hsp90, and not component this complex. Here, used coimmunoprecipitation assay demonstrate vitro-translated receptor, but Arnt, hsp90. Although...
The basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin receptor (DR) translocates to the nucleus upon binding of aromatic hydrocarbon ligands typified by dioxin, whereupon it partners Ah nuclear translocator and initiates transcription. Concurrently, ligand down-regulates levels via an unknown mechanism. In this study we show that are dependent cellular compartmentalization, with entry into leading rapid destruction DR. Ligand-induced DR translocation was bypassed adding a...
The dioxin (aryl hydrocarbon) receptor is a ligand-dependent basic helix-loop-helix (bHLH) factor that binds to xenobiotic response elements of target promoters upon heterodimerization with the bHLH partner Arnt. Here we have replaced motif heterologous DNA-binding domain create fusion proteins mediate transcriptional enhancement in yeast (Saccharomyces cerevisiae). Previously, our experiments indicated ligand-free stably associated 90-kDa heat shock protein, hsp90. To investigate role hsp90...
The intracellular dioxin receptor mediates signal transduction by and functions as a ligand-activated transcription factor. It contains basic helix-loop-helix (bHLH) motif contiguous with Per-Arnt-Sim (PAS) homology region. In extracts from nonstimulated cells the is recovered in an inducible cytoplasmic form associated 90-kDa heat shock protein (hsp90), molecular chaperone. We have reconstituted ligand-dependent activation of to DNA-binding using its bHLH-PAS partner factor Arnt expressed...