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Int. J. Mol. Sci. 2018, 19(8), 2441;

Stress-Induced Phosphorylation of Nuclear YB-1 Depends on Nuclear Trafficking of p90 Ribosomal S6 Kinase

Division of Radiobiology & Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany
German Consortium for Translational Cancer Research (DKTK), Partner Site Tuebingen and German Cancer Research Center (DKFZ), Heidelberg, Germany
Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
German Consortium for Translational Cancer Research (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany
Author to whom correspondence should be addressed.
Received: 23 July 2018 / Revised: 14 August 2018 / Accepted: 17 August 2018 / Published: 18 August 2018
(This article belongs to the Special Issue Advances and Challenges in Biomolecular Radiation Research)
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Ionizing radiation (IR) and epidermal growth factor (EGF) stimulate Y-box binding protein-1 (YB-1) phosphorylation at Ser-102 in KRAS wild-type (KRASwt) cells, whereas in KRAS mutated (KRASmut) cells, YB-1 is constitutively phosphorylated, independent of IR or EGF. YB-1 activity stimulates the repair of IR-induced DNA double-strand breaks (DSBs) in the nucleus. Thus far, the YB-1 nuclear translocation pattern after cell exposure to various cellular stressors is not clear. In the present study, we investigated the pattern of YB-1 phosphorylation and its possible translocation to the nucleus in KRASwt cells after exposure to IR, EGF treatment, and conditional expression of mutated KRAS(G12V). IR, EGF, and conditional KRAS(G12V) expression induced YB-1 phosphorylation in both the cytoplasmic and nuclear fractions of KRASwt cells. None of the stimuli induced YB-1 nuclear translocation, while p90 ribosomal s6 kinase (RSK) translocation was enhanced in KRASwt cells after any of the stimuli. EGF-induced RSK translocation to the nucleus and nuclear YB-1 phosphorylation were completely blocked by the EGF receptor kinase inhibitor erlotinib. Likewise, RSK inhibition blocked RSK nuclear translocation and nuclear YB-1 phosphorylation after irradiation and KRAS(G12V) overexpression. In summary, acute stimulation of YB-1 phosphorylation does not lead to YB-1 translocation from the cytoplasm to the nucleus. Rather, irradiation, EGF treatment, or KRAS(G12V) overexpression induces RSK activation, leading to its translocation to the nucleus, where it activates already-existing nuclear YB-1. Our novel finding illuminates the signaling pathways involved in nuclear YB-1 phosphorylation and provides a rationale for designing appropriate targeting strategies to block YB-1 in oncology as well as in radiation oncology. View Full-Text
Keywords: ionizing radiation; EGF; oncogenic KRAS; nuclear YB-1; MAPK/ERK ionizing radiation; EGF; oncogenic KRAS; nuclear YB-1; MAPK/ERK

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Tiwari, A.; Rebholz, S.; Maier, E.; Dehghan Harati, M.; Zips, D.; Sers, C.; Rodemann, H.P.; Toulany, M. Stress-Induced Phosphorylation of Nuclear YB-1 Depends on Nuclear Trafficking of p90 Ribosomal S6 Kinase. Int. J. Mol. Sci. 2018, 19, 2441.

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