C/EBPα and DEK coordinately regulate myeloid differentiation

Koleva, Rositsa I.; Ficarro, Scott B.; Radomska, Hanna S.; Carrasco-Alfonso, Marlene J.; Alberta, John A.; Webber, James T.; Luckey, Chance John; Marcucci, Guido; Tenen, Daniel G.; Marto, Jarrod A.

doi:10.1182/blood-2011-10-383083

Cited by 43 publications

(44 citation statements)

References 49 publications

(69 reference statements)

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“…logical contexts (12,13,(31)(32)(33). Continued development in mass spectrometry acquisition methods (34 -37) may provide further improvements in the performance of iTRAQbased quantitative studies.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Demonstrates Activator- and Chromatin-specific Recruitment to Promoters

Sikorski

Joo

Ficarro

et al. 2012

Journal of Biological Chemistry

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In-depth characterization of RNA polymerase II preinitiation complexes remains an important and challenging goal. We used quantitative mass spectrometry to explore context-dependent Saccharomyces cerevisiae preinitiation complex formation at the HIS4 promoter reconstituted on naked and chromatinized DNA templates. The transcription activators Gal4-VP16 and Gal4-Gcn4 recruited a limited set of chromatin-related coactivator complexes, namely the chromatin remodeler Swi/Snf and histone acetyltransferases SAGA and NuA4, suggesting that transcription stimulation is mediated through these factors. Moreover, the two activators differentially recruited the coactivator complexes, consistent with specific activator-coactivator interactions. Chromatinized templates suppressed recruitment of basal transcription factors, thereby amplifying the effect of activators, compared with naked DNA templates. This system is sensitive, highly reproducible, and easily applicable to mapping the repertoire of proteins found at any promoter.

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Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Demonstrates Activator- and Chromatin-specific Recruitment to Promoters

Sikorski

Joo

Ficarro

et al. 2012

Journal of Biological Chemistry

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“…However, and of most relevance to the present studies, DEK interacts with AP-2␣ and stimulates transactivation (88) and also interacts with C/EBP␣, an important coactivator of myeloid target genes (89), where DEK knockdown disrupts granulocyte differentiation. DEK, accompanied by AP-2␣ recruitment, becomes enriched at a site proximal to the CD21 promoter upon its transcriptional activation in B lymphocytes (90).…”

Section: Discussionmentioning

confidence: 99%

The DEK Oncoprotein Is a Critical Component of the EKLF/KLF1 Enhancer in Erythroid Cells

Lohmann

Dangeti

Soni

et al. 2015

Molecular and Cellular Biology

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e Understanding how transcriptional regulators are themselves controlled is important in attaining a complete picture of the intracellular effects that follow signaling cascades during early development and cell-restricted differentiation. We have addressed this issue by focusing on the regulation of EKLF/KLF1, a zinc finger transcription factor that plays a necessary role in the global regulation of erythroid gene expression. Using biochemical affinity purification, we have identified the DEK oncoprotein as a critical factor that interacts with an essential upstream enhancer element of the EKLF promoter and exerts a positive effect on EKLF levels. This element also binds a core set of erythroid transcription factors, suggesting that DEK is part of a tissue-restricted enhanceosome that contains BMP4-dependent and -independent components. Together with local enrichment of properly coded histones and an open chromatin domain, optimal transcriptional activation of the EKLF locus can be established. Studies of the erythroid lineage have led to the successful characterization of intracellular regulators that act as transcription factors to generate red-cell-specific expression (1). However, in many cases it remains unresolved how these factors are themselves regulated. Based on this notion, we have been studying the regulation of erythroid Krüppel-like factor (EKLF or KLF1 [2]), a zinc finger hematopoietic transcription factor that plays a global role in activation of genes critical for genetic control within the erythroid lineage (3-5). It performs this function by binding to its cognate DNA 5=CCMCRCCCN3= element and recruiting chromatin-remodeling proteins and histone modifiers.Regulation of EKLF itself is of interest because of a number of functional properties and expression characteristics. EKLF expression remains tissue specific throughout early development and in the adult. Its onset in the yolk sac is strictly limited to the mesodermal, primitive erythroid cells that populate the blood islands at the early headfold stage (embryonic day 7.5 [E7.5]), switching by E9.5 to definitive cells within the hepatic primordia and then to the red pulp of the adult spleen and the bone marrow (6). During definitive hematopoietic differentiation, EKLF is expressed at low levels in multipotent progenitors (MPP) and retains an expression pattern restricted to the common myeloid progenitor (CMP) and megakaryocyte erythroid progenitor (MEP) prior to eventual segregation to erythroid progeny (7-9).We have demonstrated that a 950-bp region adjacent to the EKLF start site of transcription, encompassing two critical erythroid hypersensitive sites (EHS1 and -2) and the proximal promoter (10), contains all the information needed for developmentally regulated, blood-cell-specific expression of a linked reporter in vivo in mice (11). The tissue specificity and enhancer properties of hypersensitive sites in this region are also seen in human erythroid cells (12). The EHS1 enhancer element contains a very highly conserved (7 species) clus...

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“…However, molecular studies of DEK oncogenicity have mostly focused on roles of DEK in interphase cells, where DEK is constitutively bound to chromatin, and functions in transcription, replication and DNA repair. 18,31,36,[53][54][55][56][57] In this study we investigated the regulation of DEK in mitosis and found that endogenous DEK is removed from chromatin in early prophase and re-associates with chromatin in telophase as outlined in Figure 8A. Importantly, DEK over-expression leads to its aberrant retention on chromatin throughout mitosis (Fig.…”

Section: Discussionmentioning

confidence: 99%

DEK over-expression promotes mitotic defects and micronucleus formation

Matrka

Hennigan

Kappes³

et al. 2015

Cell Cycle

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The DEK gene encodes a nuclear protein that binds chromatin and is involved in various fundamental nuclear processes including transcription, RNA splicing, DNA replication and DNA repair. Several cancer types characteristically over-express DEK at the earliest stages of transformation. In order to explore relevant mechanisms whereby DEK supports oncogenicity, we utilized cancer databases to identify gene transcripts whose expression patterns are tightly correlated with that of DEK. We identified an enrichment of genes involved in mitosis and thus investigated the regulation and possible function of DEK in cell division. Immunofluorescence analyses revealed that DEK dissociates from DNA in early prophase and re-associates with DNA during telophase in human keratinocytes. Mitotic cell populations displayed a sharp reduction in DEK protein levels compared to the corresponding interphase population, suggesting DEK may be degraded or otherwise removed from the cell prior to mitosis. Interestingly, DEK overexpression stimulated its own aberrant association with chromatin throughout mitosis. Furthermore, DEK colocalized with anaphase bridges, chromosome fragments, and micronuclei, suggesting a specific association with mitotically defective chromosomes. We found that DEK over-expression in both non-transformed and transformed cells is sufficient to stimulate micronucleus formation. These data support a model wherein normal chromosomal clearance of DEK is required for maintenance of high fidelity cell division and chromosomal integrity. Therefore, the overexpression of DEK and its incomplete removal from mitotic chromosomes promotes genomic instability through the generation of genetically abnormal daughter cells. Consequently, DEK over-expression may be involved in the initial steps of developing oncogenic mutations in cells leading to cancer initiation

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C/EBPα and DEK coordinately regulate myeloid differentiation

Cited by 43 publications

References 49 publications

Proteomic Analysis Demonstrates Activator- and Chromatin-specific Recruitment to Promoters

Proteomic Analysis Demonstrates Activator- and Chromatin-specific Recruitment to Promoters

The DEK Oncoprotein Is a Critical Component of the EKLF/KLF1 Enhancer in Erythroid Cells

DEK over-expression promotes mitotic defects and micronucleus formation

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