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We found that the Cu(II) and Zn(II)-specific chelator Clioquinol (10-50 microM) increased functional hypoxia-inducible factor 1alpha (HIF-1alpha) protein, leading to increased expression of its target genes, vascular endothelial growth factors and erythropoietin, in SH-SY5Y cells and HepG2 cells. Clioquinol inhibited ubiquitination of HIF-1alpha in a(More)
Targeting the oxygen-sensing mechanisms of the hypoxiainducible factor (HIF) pathway provides pharmacological ways of manipulating the HIF response. Because HIF-1 -specific prolyl-4 hydroxylases (PHDs) prime degradation of HIF-1 , we have made an effort to find a small molecule capable of upregulating the HIF pathway by inhibiting prolyl hydroxylation.(More)
Targeting the oxygen-sensing mechanisms of the hypoxiainducible factor (HIF) pathway provides pharmacological ways of manipulating the HIF response. Because HIF-1alpha-specific prolyl-4 hydroxylases (PHDs) prime degradation of HIF-1alpha, we have made an effort to find a small molecule capable of up-regulating the HIF pathway by inhibiting prolyl(More)
Posttranslational modifications of hypoxia-inducible factor-1alpha (HIF-1alpha) influence HIF-mediated transcription, likely by affecting binding to p300/cAMP-response element-binding protein (CBP). To systematically analyze the HIF-1alpha-p300/CBP interaction, we developed a fluorescence polarization-based binding assay, employing fluorescein-labeled(More)
Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) plays a central role in regulating transcriptional responses to hypoxia. This process requires hydroxylation of specific prolines in HIF-1alpha by HIF prolyl hydroxylase domain (PHD)-containing enzymes, leading to its specific interactions with von Hippel-Lindau(More)
Understanding the functional roles of all the molecules in cells is an ultimate goal of modern biology. An important facet is to understand the functional contributions from intermolecular interactions, both within a class of molecules (e.g. protein-protein) or between classes (e.g. protein-DNA). While the technologies for analyzing protein-protein and(More)
PKR (double-stranded RNA-activated protein kinase) is an important component of the innate immunity, antiviral, and apoptotic pathways. Recently, our group found that palmitate, a saturated fatty acid, is involved in apoptosis by reducing the autophosphorylation of PKR at the Thr451 residue; however, the molecular mechanism by which palmitate reduces PKR(More)
Palmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum) stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4). To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated(More)
IRE1α (Inositol-requiring enzyme 1 α), an endoplasmic reticulum (ER)-resident sensor for mammalian unfolded protein response, is a type I transmembrane protein which has a bifunctional enzyme containing kinase and RNase domains. Although the luminal domain and cytosolic domain of IRE1α are thought to play crucial roles in regulating the protein activity, no(More)