title: Regulation of A + U-rich element-directed mRNA turnover involving reversible phosphorylation of AUF1.
abstract: Proteins binding A + U-rich elements (AREs) contribute to the rapid cytoplasmic turnover of mRNAs containing these sequences. However, this process is a regulated event and may be accelerated or inhibited by myriad signal transduction systems. For example, monocyte adherence at sites of inflammation or tissue injury is associated with inhibition of ARE-directed mRNA decay, which contributes to rapid increases in cytokine and inflammatory mediator production. Here, we show that acute exposure of THP-1 monocytic leukemia cells to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate mimics several features of monocyte adherence, including rapid induction and stabilization of ARE-containing mRNAs encoding interleukin-1 beta and tumor necrosis factor alpha. Additionally, TPA treatment alters the activity of cytoplasmic complexes that bind AREs, including complexes containing the ARE-specific, mRNA-destabilizing factor, AUF1. Analyses of AUF1 from control and TPA-treated cells indicated that post-translational modifications of the major cytoplasmic isoform, p40AUF1, are altered concomitant with changes in RNA binding activity and stabilization of ARE-containing mRNAs. In particular, p40AUF1 recovered from polysomes was phosphorylated on Ser83 and Ser87 in untreated cells but lost these modifications following TPA treatment. We propose that selected signal transduction pathways may regulate ARE-directed mRNA turnover by reversible phosphorylation of polysome-associated p40AUF1.
authors.affiliation: Department of Biochemistry and Molecular Biology and Center for Fluorescence Spectroscopy, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. gwils001@umaryland.edu
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Wilson
authors.forename: Jiebo
authors.initials: J
authors.lastname: Lu
authors.forename: Kristina
authors.initials: K
authors.lastname: Sutphen
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.forename: Yung
authors.initials: Y
authors.lastname: Huynh
authors.forename: Gary
authors.initials: G
authors.lastname: Brewer
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002448:Cell Adhesion; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007700:Kinetics; D007938:Leukemia / Q000378:metabolism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011132:Polyribosomes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D007375:Interleukin-1; D010455:Peptides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D012694:Serine; D012260:Ribonucleases; D013755:Tetradecanoylphorbol Acetate