Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity
| Autor: | Edurne Berra, Paul N. Moynagh, Jacques Pouysségur, Cormac T. Taylor, Amandine Ginouvès, Katrina M. Comerford, Kathleen T. Fitzgerald, Jens Erik Nielsen, Catherine Godson, Fergal Seeballuck, Eoin P. Cummins |
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| Přispěvatelé: | Conway Institute of Biomolecular and Biomedical Research, University College Dublin [Dublin] (UCD), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA) |
| Rok vydání: | 2006 |
| Předmět: |
MESH: Cell Nucleus
Molecular Sequence Data MESH: Cell Hypoxia Procollagen-Proline Dioxygenase MESH: NF-kappa B [SDV.CAN]Life Sciences [q-bio]/Cancer MESH: Amino Acid Sequence IκB kinase Biology Cell Line Hydroxylation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans MESH: Protein Binding [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Amino Acid Sequence MESH: I-kappa B Kinase Transcription factor 030304 developmental biology Cell Nucleus 0303 health sciences MESH: Humans MESH: Molecular Sequence Data Multidisciplinary Tumor Necrosis Factor-alpha NF-kappa B I-Kappa-B Kinase Biological Sciences Hypoxia (medical) Molecular biology Cell Hypoxia I-kappa B Kinase MESH: Cell Line Cell biology IκBα chemistry MESH: Tumor Necrosis Factor-alpha 030220 oncology & carcinogenesis Procollagen-proline dioxygenase medicine.symptom Signal transduction Protein Binding MESH: Procollagen-Proline Dioxygenase |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2006, 103 (48), pp.18154-9. ⟨10.1073/pnas.0602235103⟩ |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFkappaB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFkappaB through a pathway involving activation of IkappaB kinase-beta (IKKbeta) leading to phosphorylation-dependent degradation of IkappaBalpha and liberation of NFkappaB. Furthermore, through increasing the pool and/or activation potential of IKKbeta, hypoxia amplifies cellular sensitivity to stimulation with TNFalpha. Within its activation loop, IKKbeta contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NFkappaB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFkappaB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFkappaB. Hypoxia increases both the expression and activity of IKKbeta, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKbeta hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFkappaB activity through decreased PHD-dependent hydroxylation of IKKbeta, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways. |
| Databáze: | OpenAIRE |
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