title: Hypoxia-inducible factor 1 alpha is regulated by RBM38, a RNA-binding protein and a p53 family target, via mRNA translation.
abstract: Hypoxia-inducible factor 1 (HIF1), a heterodimeric transcription factor, consists of HIF1α and HIF1β and is necessary for cell growth and survival under a hypoxic condition. Thus, the level and activity of HIF1α needs to be tightly controlled. Indeed, HIF1α protein stability is controlled by prolyl hydroxylase and von Hippel-Lindau-mediated proteosomal degradation. However, it remains unclear whether HIF1α expression is controlled by other pathways. Here, we showed that RNA-binding protein RBM38, a target of the p53 family, regulates HIF1α expression via mRNA translation. Specifically, we showed that under a hypoxic condition, ectopic expression of RBM38 decreased, whereas knockdown of RBM38 increased, the level of HIF1α protein. We also showed that the rate of de novo HIF1α protein synthesis was increased by knockdown of RBM38. Additionally, we showed that RBM38 directly bound to HIF1α 5' and 3'UTRs. Consistently, we showed that the rate of mRNA translation for a heterologous reporter that carries HIF1α 5'and/or 3'UTRs was increased upon knockdown of RBM38. Furthermore, we showed that knockdown of RBM38 increased, whereas ectopic expression of RBM38 decreased, the binding of eIF4E to HIF1α mRNA. Together, our data suggest that RBM38 is a novel translational regulator of HIF1α under a hypoxic condition.
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Teng
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Yin
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, CA.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D047468:Immunoprecipitation; D014176:Protein Biosynthesis / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C515435:RBM38 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins