科研之友
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摘要
CCAAT/enhancer-binding Protein beta (C/EBP beta) is a member of the bZIP transcription factor family that is expressed in various tissues, including cells of the hematopoietic system. C/EBP beta 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/EBP beta is negatively regulated by the transcriptional co-repressor Daxx. C/EBP beta 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/EBP beta. Coexpression of C/EBP beta changed the sub-nuclear Daxx distribution pattern from predominantly POD-localized to nucleoplasmic. Daxx suppressed basal and p300-enhanced transcriptional activity of C/EBP beta. Furthermore, Daxx decreased the C/EBP beta dependent phosphorylation of p300, which in turn was associated with a diminished level of p300-mediated C/EBP beta acetylation. Co-expression of promyelocytic leukemia protein abrogated the repressive effect of Daxx on C/EBP beta as well as the direct interaction of Daxx and C/EBP beta, presumably by re-recruiting Daxx to PML-oncogenic domains. In acute promyelocytic leukemia (APL) cells, C/EBP beta 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/EBP beta fraction associated with Daxx suggesting a relief of Daxx-dependent C/EBP beta repression as an important molecular event leading to APL cell differentiation. Overall, our data identify Daxx as a new negative regulator of C/EBP beta and provide first clues for a link between abrogation of Daxx-C/EBP beta complex formation and APL remission.
- 出版日期2009-10-16
