The CCAAT Enhancer-binding Protein α (C/EBPα) Requires a SWI/SNF Complex for Proliferation Arrest

Müller, Christine; Calkhoven, Cornelis F.; Sha, Xiaojing; Leutz, Achim

doi:10.1074/jbc.m312709200

Cited by 83 publications

(69 citation statements)

References 59 publications

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“…Potential antagonistic protein interactions leading to a block in C/EBPa function in AML have been well implicated in recent findings (Pabst et al, 2001a;Vangala et al, 2003;Zheng et al, 2004). Interestingly, C/EBPa also functions via direct proteinprotein interactions in normal stem cell development (Behre et al, 2002a;D'Alo et al, 2003;Muller et al, 2004); PU.1 and c-Jun inactivation (Rangatia et al, 2002;Reddy et al, 2002), E2F repression (Porse et al, 2001), and cdk2 and cdk4 inhibition (Wang et al, 2001) by C/EBPa are all accompanied by direct protein-protein interactions. Moreover, different protein partners of C/EBPa in young and old mice livers itself demonstrate the importance of protein-protein interactions during ageing (Iakova et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

et al. 2006

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Functional inactivation of transcription factors in hematopoietic stem cell development is involved in the pathogenesis of acute myeloid leukemia (AML). Stem cell regulator C/enhancer binding protein (EBP)a is among such transcription factors known to be inactive in AML. This is either due to mutations or inhibition by protein-protein interactions. Here, we applied a mass spectrometry-based proteomic approach to systematically identify putative co-activator proteins interacting with the DNA-binding domain (DBD) of C/EBP transcription factors. In our proteomic screen, we identified c-Jun N-terminal kinase (JNK) 1 among others such as PAK6, MADP-1, calmodulin-like skin proteins and ZNF45 as proteins interacting with DBD of C/EBPs from nuclear extract of myelomonocytic U937 cells. We show that kinase JNK1 physically interacts with DBD of C/EBPa in vitro and in vivo. Furthermore, we show that active JNK1 inhibits ubiquitination of C/EBPa possibly by phosphorylating in its DBD. Consequently, JNK1 prolongs C/EBPa protein half-life leading to its enhanced transactivation and DNA-binding capacity. In certain AML patients, however, the JNK1 mRNA expression and its kinase activity is decreased which suggests a possible reason for C/EBPa inactivation in AML. Thus, we report the first proteomic screen of C/EBP-interacting proteins, which identifies JNK1 as positive regulator of C/EBPa.

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Section: Introductionmentioning

confidence: 97%

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

et al. 2006

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“…7). TAD4 is known to be essential for direct binding of C/EBP-TAD to the TAF2B and TBP components of the general RNA polymerase II transcriptional apparatus (70) and also for interaction of C/EBP␤ with CBP and p300 transcriptional coactivators and SWI/SNF chromatin remodeling factors (73)(74)(75)(76)(77). Thus, GADD45␤ activation of C/EBP␤-TAD4 function via MTK1/MKK3/6/p38 signaling suggests a general mechanism for facilitating processes driven by transcription factors containing TAD4-like domains, such as c-Jun (72).…”

Section: Gadd45␤ Regulation Of Genes Involved In Terminal Chondrocytementioning

confidence: 99%

GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

Tsuchimochi

Otero

Dragomir

et al. 2010

Journal of Biological Chemistry

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GADD45␤ (growth arrest-and DNA damage-inducible) interacts with upstream regulators of the JNK and p38 stress response kinases. Previously, we reported that the hypertrophic zone of the Gadd45␤ ؊/؊ mouse embryonic growth plate is compressed, and expression of type X collagen (Col10a1) and matrix metalloproteinase 13 (Mmp13) genes is decreased. Herein, we report that GADD45␤ enhances activity of the proximal Col10a1 promoter, which contains evolutionarily conserved AP-1, cAMP-response element, and C/EBP half-sites, in synergism with C/EBP family members, whereas the MMP13 promoter responds to GADD45␤ together with AP-1, ATF, or C/EBP family members. C/EBP␤ expression also predominantly co-localizes with GADD45␤ in the embryonic growth plate. Moreover, GADD45␤ enhances C/EBP␤ activation via MTK1, MKK3, and MKK6, and dominant-negative p38␣apf, but not JNKapf, disrupts the combined trans-activating effect of GADD45␤ and C/EBP␤ on the Col10a1 promoter. Importantly, GADD45␤ knockdown prevents p38 phosphorylation while decreasing Col10a1 mRNA levels but does not affect C/EBP␤ binding to the Col10a1 promoter in vivo, indicating that GADD45␤ influences the transactivation function of DNA-bound C/EBP␤. In support of this conclusion, we show that the evolutionarily conserved TAD4 domain of C/EBP␤ is the target of the GADD45␤-dependent signaling. Collectively, we have uncovered a novel molecular mechanism linking GADD45␤ via the MTK1/MKK3/6/p38 axis to C/EBP␤-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes.

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Section: Chromatin Remodelingmentioning

confidence: 99%

“…Among them, the SWI/ SNF complexes, which consist of one or more catalytic subunits: Brahma (Brm), Brahma-related gene 1 protein (Brg1) or Breastovarian cancer susceptibility protein 1 (Brca1), and polycomb repressors (Bmi-1), play roles in neural development. Muller et al found that the SWI/SNF complexes were also associated with the cell differentiation and cell cycle arrest mediated by C/EBP [38] .The SWI/SNF complexes interact with HATs or HDACs and/or sequence-specific transcription factors to activate or repress the target genes. Kondo et al suggest that the conversion of oligodendrocyte precursor cells to neural-stem-like cells is associated with recruitment of the Brca1 and Brm (the catalytic subunit in a subset of SWI/ SNF) to the promoter of a key transcription factor gene Sox2, which involves in maintaining the proliferation of NSCs [39] by methylation at K4 and acetylation at K9 in the histone H3 of the promoter.…”

mentioning

confidence: 99%

Epigenetics and neural stem cell commitment

Zhu

2007

Neurosci. Bull.

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Neural stem cell is presently the research hotspot in neuroscience. Recent progress indicates that epigenetic modulation is closely related to the self-renewal and differentiation of neural stem cell. Epigenetics refer to the study of mitotical/meiotical heritage changes in gene function that cannot be explained by changes in the DNA sequence. Major epigenetic mechanisms include DNA methylation, histone modification, chromatin remodeling, genomic imprinting, and non-coding RNA. In this review, we focus on the new insights into the epigenetic mechanism for neural stem cells fate.Key words: stem cells; epigenesis; neuron restrictive silencer element; genomic imprinting; H19; non-coding RNA Epigenetics, a newly arising subject in genetics, refers to the heritable changes of gene function that would ultimately result in cellular specification transformation without altering the genome sequence. In 1942, Waddington CH firstly raised the term "epigenetics", pointing out that it was related to genetics and mainly dealt with the links between genetic identity and epigenetic identity. Later, Holiday R drew more systemic conclusion that the objective of epigenetics was to study the heritable pattern of gene expression change without DNA sequence alteration [1] . The epigenetic mechanisms cover a wide range, containing DNA methylation, histone modification (such as acetylation), chromatin remodeling, genomic imprinting, and regulatory non-coding RNAs. These epigenetic factors are closely related to regulate gene expression (Fig. 1). Recently, more and more investigations have shown that epigenetic modifications play important roles in neural stem cell (NSC) commitment [2,3] , which would be discussed in this review. DNA methylationOne class of epigenetic modifications is DNA cytosine methylation, which consistently associated with diverse gene regulatory processes, for instance, genomic imprinting [4] . In vertebrates, DNA methylation mainly takes place at CpG dinucleotides. Clusters of CpG dimer known as CpG islands are located on the region of gene promoter. During the process of DNA methylation, cytosine is out of DNA double helix and enters the split that binds to the cytosine methyltransferase. The latter transfers the methyl of sadenosylmethionine (SAM) to the 5' of cytosine, forming 5-methyl-cytosine. DNA methylation is carried out by the DNA methyl transferase (DNMT) protein family, which is split into three kinds in mammals: DNMT1, DNMT2 and DNMT3. DNMT3a and DNMT3b [5] was originally described as de novo methyltransferases; DNMT1 could maintain methylation; and DNMT2 was found as a homologue to the Schizosac-charomyces pombe DNA methyltransferase.DNA methylation-mediated gene silencing is regulated through two mechanisms: 1, the methylation at CpG sites blocks transcription factor binding and leads to transcriptional inactivation; and 2, methyl-CpGs are bound by a family of methyl-CpG binding proteins (MBDs), including MBD1-4 and MeCP2. The MBDs binding and the further recruitment of histone deacety...

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The CCAAT Enhancer-binding Protein α (C/EBPα) Requires a SWI/SNF Complex for Proliferation Arrest

Cited by 83 publications

References 59 publications

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

Epigenetics and neural stem cell commitment

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