title: Transcriptional regulation of immediate-early gene response by THOC5, a member of mRNA export complex, contributes to the M-CSF-induced macrophage differentiation.
abstract: Hematopoiesis and commitment to a restricted lineage are guided by a timely expressed set of cytokine receptors and their downstream transcription factors. A member of the mRNA export complex, THOC5 (suppressors of the transcriptional defects of hpr1 delta by overexpression complex 5) is a substrate for several tyrosine kinases such as macrophage colony-stimulating factor (M-CSF) receptor and various leukemogenic tyrosine kinases, such as Bcr-Abl, or NPM-ALK. THOC5 tyrosine phosphorylation is elevated in stem cells from patients with chronic myeloid leukemia, suggesting that THOC5 may be involved in leukemia development. THOC5 is also an essential element in the maintenance of hematopoiesis in adult mice. In this report, we show that THOC5 is located in the nuclear speckles, and that it is translocated from the nucleus to cytoplasm during M-CSF-induced bone marrow-derived macrophage differentiation. Furthermore, we have identified THOC5 target genes by trancriptome analysis, using tamoxifen-inducible THOC5 knockout macrophages. Although only 99 genes were downregulated in THOC5-depleted macrophages, half of the genes are involved in differentiation and/or migration. These include well-known regulators of myeloid differentiation inhibitor of DNA binding (Id)1, Id3, Smad family member 6 (Smad6) and Homeobox (Hox)A1. In addition, a subset of M-CSF-inducible genes, such as Ets family mRNAs are THOC5 target mRNAs. Upon depletion of THOC5, unspliced v-ets erythroblastosis virus E26 oncogene homolog (Ets1) mRNA was accumulated in the nucleus. Furthermore, THOC5 was recruited to chromatin where Ets1 was transcribed and bound to unspliced and spliced Ets1 transcripts, indicating that THOC5 has a role in processing/export of M-CSF-inducible genes. In conclusion, regulation of immediate-early gene response by THOC5, a member of mRNA export complex contributes to the M-CSF-induced macrophage differentiation.
authors.affiliation: Institut fuer Biochemie, OE4310, Medizinische Hochschule Hannover, Carl-Neuberg-Street 1, Hannover D-30623, Germany.
authors.forename: D D H
authors.initials: DD
authors.lastname: Tran
authors.forename: S
authors.initials: S
authors.lastname: Saran
authors.forename: O
authors.initials: O
authors.lastname: Dittrich-Breiholz
authors.forename: A J K
authors.initials: AJ
authors.lastname: Williamson
authors.forename: S
authors.initials: S
authors.lastname: Klebba-Färber
authors.forename: A
authors.initials: A
authors.lastname: Koch
authors.forename: M
authors.initials: M
authors.lastname: Kracht
authors.forename: A D
authors.initials: AD
authors.lastname: Whetton
authors.forename: T
authors.initials: T
authors.lastname: Tamura
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D034443:RNA Transport / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics
chemical_list: C494042:Ets1 protein, mouse; D009687:Nuclear Proteins; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; C559981:THOC5 protein, mouse; D016173:Macrophage Colony-Stimulating Factor