Aryl hydrocarbon receptor nuclear translocator

About: Aryl hydrocarbon receptor nuclear translocator is a research topic. Over the lifetime, 1395 publications have been published within this topic receiving 110873 citations. The topic is also known as: HIF-1-beta & HIF-1beta.

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension

Abstract: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.

Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.

Abstract: Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.

The aryl hydrocarbon receptor complex.

Abstract: The heterorneric unliga nded aryl hydrocarbon receptor complex (AHRC) con­ ta ins the aryl hydrocarbon receptor monomer (AHR). Binding of polycyclic or ha loge nated aromatic hydrocarbon (PAH and HAH) ligand causes release of AHR, which then associates with the AHR nuclear translocator protein (ARNT) to generate the heterodimeric "transformed" AHRC, AHR and ARNT belong to a novel subclass of basic helix-loop-helix -containing transcription factors. The transformed AHRC binds xenobiotic responsive elements in re­ sponsive genes and turns on their transcr iption, Certain of these genes encode enzymes involved in the metabol ic activation of PAHs to mutagenic deriva­ tives. HAHs are not genotoxic: Their pathogen icity depends on the AHRC but not on their metab olism. Current rese arch includes investigations dir ected towards delineating the pathways of HAH pathogenesis, ascer taining whether AHR can mediate signal transduction independently of DNA binding, under­ standing the mechanism of transcriptional activation, and investigating the potential roles of AHR and ARNT in development.

HIF-1 alpha is required for solid tumor formation and embryonic vascularization.

Abstract: The transcriptional response to lowered oxygen levels is mediated by the hypoxia-inducible transcription factor (HIF-1), a heterodimer consisting of the constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) and the hypoxic response factor HIF-1alpha. To study the role of the transcriptional hypoxic response in vivo we have targeted the murine HIF-1alpha gene. Loss of HIF-1alpha in embryonic stem (ES) cells dramatically retards solid tumor growth; this is correlated with a reduced capacity to release the angiogenic factor vascular endothelial growth factor (VEGF) during hypoxia. HIF-1alpha null mutant embryos exhibit clear morphological differences by embryonic day (E) 8.0, and by E8.5 there is a complete lack of cephalic vascularization, a reduction in the number of somites, abnormal neural fold formation and a greatly increased degree of hypoxia (measured by the nitroimidazole EF5). These data demonstrate the essential role of HIF-1alpha in controlling both embryonic and tumorigenic responses to variations in microenvironmental oxygenation.