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sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism

Kunze, Michael M. and Benz, Fabienne and Brauß, Thilo F. and Lampe, Sebastian and Weigand, Julia E. and Braun, Johannes and Richter, Florian M. and Wittig, Ilka and Brüne, Bernhard and Schmid, Tobias (2016):
sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism.
In: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1859 (7), pp. 848-859. Elsevier, ISSN 0006-3002,
DOI: 10.1016/j.bbagrm.2016.05.005,
[Article]

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.

Item Type: Article
Erschienen: 2016
Creators: Kunze, Michael M. and Benz, Fabienne and Brauß, Thilo F. and Lampe, Sebastian and Weigand, Julia E. and Braun, Johannes and Richter, Florian M. and Wittig, Ilka and Brüne, Bernhard and Schmid, Tobias
Title: sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism
Language: English
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.

Journal or Publication Title: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Journal volume: 1859
Number: 7
Publisher: Elsevier
Divisions: 10 Department of Biology
10 Department of Biology > RNA Biochemistry
Date Deposited: 05 Mar 2021 07:36
DOI: 10.1016/j.bbagrm.2016.05.005
Official URL: https://www.sciencedirect.com/science/article/pii/S187493991...
Identification Number: pmid:27168114
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