Abstract
Although quantitative and qualitative granulocyte defects have been described in myelodysplastic syndromes (MDS), the underlying molecular basis of granulocyte dysfunction in MDS is largely unknown. We recently found that FOS mRNA elevation under translation-inhibiting stimuli was significantly smaller in granulocytes from MDS patients than in healthy individuals. The aim of this study is to clarify the cause of the impaired FOS induction in MDS. We first examined the mechanisms of FOS mRNA elevation using granulocytes from healthy donors cultured with the translation inhibitor emetine. Emetine increased both transcription and mRNA stability of FOS. p38 MAPK inhibition abolished the emetine-induced increase of FOS transcription but did not affect FOS mRNA stabilization. The binding of an AU-rich element (ARE)-binding protein HuR to FOS mRNA containing an ARE in 3'UTR was increased by emetine, and the knockdown of HuR reduced the FOS mRNA stabilizing effect of emetine. We next compared the emetine-induced transcription and mRNA stabilization of FOS between MDS patients and healthy controls. Increased rates of FOS transcription by emetine were similar in MDS and controls. In the absence of emetine, FOS mRNA decayed to nearly 17% of initial levels in 45 min in both groups. In the presence of emetine, however, 76.7±19.8% of FOS mRNA remained after 45 min in healthy controls, versus 37.9±25.5% in MDS (P<0.01). To our knowledge, this is the first report demonstrating attenuation of stress-induced FOS mRNA stabilization in MDS granulocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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Adult
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Aged
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Aged, 80 and over
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Base Sequence
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Case-Control Studies
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ELAV Proteins / metabolism
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Emetine / pharmacology
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Female
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Granulocytes / drug effects
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Granulocytes / enzymology
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Granulocytes / metabolism*
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Humans
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Lipopolysaccharides / pharmacology
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Male
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Middle Aged
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Molecular Sequence Data
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Myelodysplastic Syndromes / genetics*
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Protein Binding / drug effects
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Protein Binding / genetics
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Protein Biosynthesis* / drug effects
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-fos / biosynthesis*
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Proto-Oncogene Proteins c-fos / genetics*
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RNA Stability / drug effects
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RNA Stability / genetics*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transcription, Genetic / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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3' Untranslated Regions
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ELAV Proteins
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Lipopolysaccharides
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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Granulocyte-Macrophage Colony-Stimulating Factor
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p38 Mitogen-Activated Protein Kinases
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Emetine
Grants and funding
This work was supported by Grant-in-Aid for Scientific Research (C) [MO23591400] to YS from Japan Society for the Promotion of Science, Grants-in-Aid for Fukushima Medical University Research Project [KPJ20005] to YS, and Smoking Research Foundation [Grant KI18003] to JK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.