期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 478, 期 2, 页码 982-987出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2016.08.064
关键词
Hypoxia; HRE; Cold shock protein; YB-1; Gene regulation
资金
- Roche Foundation for Anemia Research (RoFAR) [SFB854, A1, Me1365/7-2, 9-1]
- START project of the Medical Faculty at RWTH Aachen University
- DFG [RA 1927/5-1, RA 740/8-1]
- Interdisciplinary Center for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF) [E7-7]
Hypoxia-dependent gene regulation is largely orchestrated by hypoxia-inducible factors (HIFs), which associate with defined nucleotide sequences of hypoxia-responsive elements (HREs). Comparison of the regulatory HRE within the 3' enhancer of the human erythropoietin (EPO) gene with known binding motifs for cold shock protein Y-box (YB) protein-1 yielded strong similarities within the Y-box element and 3' adjacent sequences. DNA binding assays confirmed YB-1 binding to both, single- and double stranded HRE templates. Under hypoxia, we observed nuclear shuttling of YB-1 and coimmunoprecipitation assays demonstrated that YB-1 and HIF-1 alpha physically interact with each other. Cellular YB-1 depletion using siRNA significantly induced hypoxia-dependent EPO production at both, promoter and mRNA level. Vice versa, overexpressed YB-1 significantly reduced EPO-HRE-dependent gene transcription, whereas this effect was minor under normoxia. HIF-la overexpression induced hypoxia-dependent gene transcription through the same element and accordingly, co-expression with YB-1 reduced HIF-1 alpha-mediated EPO induction under hypoxic conditions. Taken together, we identified YB-1 as a novel binding factor for HREs that participates in fine-tuning of the hypoxia transcriptome. (C) 2016 Elsevier Inc. All rights reserved.
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