title: Daxx is a transcriptional repressor of CCAAT/enhancer-binding protein beta.
abstract: CCAAT/enhancer-binding Protein beta (C/EBPbeta) is a member of the bZIP transcription factor family that is expressed in various tissues, including cells of the hematopoietic system. C/EBPbeta is involved in tissue-specific gene expression and thereby takes part in fundamental cellular processes such as proliferation and differentiation. Here, we show that the activity of C/EBPbeta is negatively regulated by the transcriptional co-repressor Daxx. C/EBPbeta was found to directly interact with Daxx after overexpression as well as on the endogenous level. Glutathione S-transferase pulldown assays showed that Daxx binds via amino acids 190-400 to the C-terminal part of C/EBPbeta. Co-expression of C/EBPbeta changed the sub-nuclear Daxx distribution pattern from predominantly POD-localized to nucleoplasmic. Daxx suppressed basal and p300-enhanced transcriptional activity of C/EBPbeta. Furthermore, Daxx decreased the C/EBPbeta-dependent phosphorylation of p300, which in turn was associated with a diminished level of p300-mediated C/EBPbeta acetylation. Co-expression of promyelocytic leukemia protein abrogated the repressive effect of Daxx on C/EBPbeta as well as the direct interaction of Daxx and C/EBPbeta, presumably by re-recruiting Daxx to PML-oncogenic domains. In acute promyelocytic leukemia (APL) cells, C/EBPbeta activity is known to be required for all-trans-retinoic acid-induced cell differentiation and disease remission. We show that all-trans-retinoic acid as well as arsenic trioxide treatment leads to a reduced C/EBPbeta fraction associated with Daxx suggesting a relief of Daxx-dependent C/EBPbeta repression as an important molecular event leading to APL cell differentiation. Overall, our data identify Daxx as a new negative regulator of C/EBPbeta and provide first clues for a link between abrogation of Daxx-C/EBPbeta complex formation and APL remission.
authors.affiliation: Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Strasse 2, Münster D-48149, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Wethkamp
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Klempnauer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002454:Cell Differentiation; D056970:Co-Repressor Proteins; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic; D006367:HeLa Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011784:Quail; D014212:Tretinoin / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D022782:CCAAT-Enhancer-Binding Protein-beta; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D014212:Tretinoin; D050880:p300-CBP Transcription Factors
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