title: sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism.
abstract: Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions. This mechanism is controlled by IRES trans-acting factors (ITAF), i.e. by RNA-binding proteins, which interact with and determine the activity of selected IRESs. We aimed at characterizing the translational regulation of the IL-33 decoy receptor sST2, which was enhanced by fibroblast growth factor 2 (FGF2). We identified and verified an IRES within the 5'UTR of sST2. Furthermore, we found that MEK/ERK signaling contributes to FGF2-induced, sST2-IRES activation and translation. Determination of the sST2-5'UTR structure by in-line probing followed by deletion analyses identified 23 nucleotides within the sST2-5'UTR to be required for optimal IRES activity. Finally, we show that the RNA-binding protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds to the sST2-5'UTR, acts as an ITAF, and thus controls the activity of the sST2-IRES and consequently sST2 translation. Specifically, FGF2 enhances nuclear-cytoplasmic translocation of hnRNP A1, which requires intact MEK/ERK activity. In summary, we provide evidence that the sST2-5'UTR contains an IRES element, which is activated by a MEK/ERK-dependent increase in cytoplasmic localization of hnRNP A1 in response to FGF2, enhancing the translation of sST2.
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kunze
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Benz
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Thilo F
authors.initials: TF
authors.lastname: Brauß
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lampe
authors.affiliation: Department of Biology, Technical University Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Weigand
authors.affiliation: Department of Biology, Technical University Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Braun
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Florian M
authors.initials: FM
authors.lastname: Richter
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany. Electronic address: T.Schmid@biochem.uni-frankfurt.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmid
mesh_terms: D020121:5' Untranslated Regions / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000502:physiology*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067556:Internal Ribosome Entry Sites / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D061986:MCF-7 Cells; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D012995:Solubility
chemical_list: D020121:5' Untranslated Regions; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067556:Internal Ribosome Entry Sites; D011956:Receptors, Cell Surface; D016222:Fibroblast Growth Factor 2
keywords: IRES; ITAF; MEK/ERK; RNA-binding protein; hnRNP A1