DEAD Box Protein Family Member DDX28 Is a Negative Regulator of Hypoxia-Inducible Factor 2α- and Eukaryotic Initiation Factor 4E2-Directed Hypoxic Translation
| Autor: | Sonia L. Evagelou, Erin J. Specker, James Uniacke, Olivia Bebenek |
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| Rok vydání: | 2020 |
| Předmět: |
DEAD box
Regulator Biology DEAD-box RNA Helicases Small hairpin RNA 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Eukaryotic initiation factor Oxygen homeostasis Basic Helix-Loop-Helix Transcription Factors Humans Gene silencing RNA Small Interfering Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences Messenger RNA Cell Biology Cell Hypoxia 3. Good health Cell biology Oxygen Eukaryotic Initiation Factor-4E Gene Expression Regulation Protein Biosynthesis 030220 oncology & carcinogenesis RNA Interference Glioblastoma Research Article |
| Zdroj: | Mol Cell Biol |
| ISSN: | 1098-5549 |
| Popis: | Hypoxia is a deficiency in oxygen delivery to tissues and is connected to physiological and pathophysiological processes such as embryonic development and cancer. The master regulators of oxygen homeostasis in mammalian cells are the heterodimeric hypoxia-inducible transcription factors 1 and 2 (HIF-1 and HIF-2, respectively). The oxygen-labile HIF-2α subunit has been implicated not only in transcription but also as a regulator of eukaryotic initiation factor 4E2 (eIF4E2)-directed hypoxic translation. Here, we have identified the DEAD box protein family member DDX28 as an interactor and negative regulator of HIF-2α that suppresses HIF-2α’s ability to activate eIF4E2-directed translation. Stable silencing of DDX28 via short hairpin RNA (shRNA) in hypoxic human U87MG glioblastoma cells caused an increase of eIF4E2 binding to the m(7)GTP cap structure and the translation of eIF4E2 target mRNAs (including the HIF-2α mRNA itself). DDX28 depletion elevated nuclear and cytoplasmic HIF-2α protein, but HIF-2α transcriptional activity did not increase, possibly due to its already high nuclear abundance in hypoxic control cells. Depletion of DDX28 conferred a proliferative advantage to hypoxic, but not normoxic, cells. DDX28 protein levels are reduced in several cancers, including gliomas, relative to levels in normal tissue. Therefore, we uncover a regulatory mechanism for this potential tumor suppressor in the repression of HIF-2α- and eIF4E2-mediated translation activation of oncogenic mRNAs. |
| Databáze: | OpenAIRE |
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