19 results on '"Marianne Quaas"'
Search Results
2. The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1
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Romy Winkler, Marianne Quaas, Stefan Glasmacher, Uwe Wolfrum, Torsten Thalheim, Jörg Galle, Knut Krohn, Thomas M. Magin, and Gabriela Aust
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GPR115 ,epidermis ,keratinocyte ,KRT1 ,Cytology ,QH573-671 - Abstract
Among the 33 human adhesion G-protein-coupled receptors (aGPCRs), a unique subfamily of GPCRs, only ADGRF4, encoding GPR115, shows an obvious skin-dominated transcriptomic profile, but its expression and function in skin is largely unknown. Here, we report that GPR115 is present in a small subset of basal and in most suprabasal, noncornified keratinocytes of the stratified epidermis, supporting epidermal transcriptomic data. In psoriatic skin, characterized by hyperproliferation and delayed differentiation, the expression of GPR115 and KRT1/10, the fundamental suprabasal keratin dimer, is delayed. The deletion of ADGRF4 in HaCaT keratinocytes grown in an organotypic mode abrogates KRT1 and reduces keratinocyte stratification, indicating a role of GPR115 in epidermal differentiation. Unexpectedly, endogenous GPR115, which is not glycosylated and is likely not proteolytically processed, localizes intracellularly along KRT1/10-positive keratin filaments in a regular pattern. Our data demonstrate a hitherto unknown function of GPR115 in the regulation of epidermal differentiation and KRT1.
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- 2022
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3. Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine
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Maria Herberg, Susann Siebert, Marianne Quaas, Torsten Thalheim, Karen Rother, Michelle Hussong, Janine Altmüller, Christiane Kerner, Joerg Galle, Michal R. Schweiger, and Gabriela Aust
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Intestine ,Mismatch repair deficiency ,Radiation ,Msh2 ,Histone H3 methylation ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Mismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we quantified genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2 LoxP/LoxP (Msh2 −/− ) mice months before tumor onset. Results Histone H3 methylation increases in Msh2 −/− compared to control Msh2 +/+ mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2 +/+ mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2 +/+ mice 4 weeks after a single-radiation hit, whereas radiation of Msh2 −/− mice left their histone methylation profiles almost unchanged. Conclusions MMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage.
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- 2019
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4. To Detach, Migrate, Adhere, and Metastasize: CD97/ADGRE5 in Cancer
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Gabriela Aust, Leyu Zheng, and Marianne Quaas
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CD97 ,ADGRE5 ,EGF-TM7 ,aGPCR ,cancer ,tumor ,Cytology ,QH573-671 - Abstract
Tumorigenesis is a multistep process, during which cells acquire a series of mutations that lead to unrestrained cell growth and proliferation, inhibition of cell differentiation, and evasion of cell death. Growing tumors stimulate angiogenesis, providing them with nutrients and oxygen. Ultimately, tumor cells invade the surrounding tissue and metastasize; a process responsible for about 90% of cancer-related deaths. Adhesion G protein-coupled receptors (aGPCRs) modulate the cellular processes closely related to tumor cell biology, such as adhesion and detachment, migration, polarity, and guidance. Soon after first being described, individual human aGPCRs were found to be involved in tumorigenesis. Twenty-five years ago, CD97/ADGRE5 was discovered to be induced in one of the most severe tumors, dedifferentiated anaplastic thyroid carcinoma. After decades of research, the time has come to review our knowledge of the presence and function of CD97 in cancer. In summary, CD97 is obviously induced or altered in many tumor entities; this has been shown consistently in nearly one hundred published studies. However, its high expression at circulating and tumor-infiltrating immune cells renders the systemic targeting of CD97 in tumors difficult.
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- 2022
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5. Adhesion GPCR GPR56 Expression Profiling in Human Tissues
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Fyn Kaiser, Markus Morawski, Knut Krohn, Nada Rayes, Cheng-Chih Hsiao, Marianne Quaas, and Gabriela Aust
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GPR56 ,ADGRG1 ,thyroid ,microglia ,Cytology ,QH573-671 - Abstract
Despite the immense functional relevance of GPR56 (gene ADGRG1) in highly diverse (patho)physiological processes such as tumorigenesis, immune regulation, and brain development, little is known about its exact tissue localization. Here, we validated antibodies for GPR56-specific binding using cells with tagged GPR56 or eliminated ADGRG1 in immunotechniques. Using the most suitable antibody, we then established the human GPR56 tissue expression profile. Overall, ADGRG1 RNA-sequencing data of human tissues and GPR56 protein expression correlate very well. In the adult brain especially, microglia are GPR56-positive. Outside the central nervous system, GPR56 is frequently expressed in cuboidal or highly prismatic secreting epithelia. High ADGRG1 mRNA, present in the thyroid, kidney, and placenta is related to elevated GPR56 in thyrocytes, kidney tubules, and the syncytiotrophoblast, respectively. GPR56 often appears in association with secreted proteins such as pepsinogen A in gastric chief cells and insulin in islet β-cells. In summary, GPR56 shows a broad, not cell-type restricted expression in humans.
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- 2021
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6. Epigenetic Drifts during Long-Term Intestinal Organoid Culture
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Torsten Thalheim, Susann Siebert, Marianne Quaas, Maria Herberg, Michal R. Schweiger, Gabriela Aust, and Joerg Galle
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age-related drifts ,mouse small intestine ,MMR-deficient mice ,histone modification ,H3K4me3 ,H3K27me3 ,Cytology ,QH573-671 - Abstract
Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and accessible to genetic engineering. Thus, they represent an optimal tool for studying the mechanisms of tissue maintenance and aging. Long-term expansion under standard growth conditions, however, is accompanied by changes in the growth pattern and kinetics. As a potential explanation of these alterations, epigenetic drifts in organoid culture have been suggested. Here, we studied histone tri-methylation at lysine 4 (H3K4me3) and 27 (H3K27me3) and transcriptome profiles of intestinal organoids derived from mismatch repair (MMR)-deficient and control mice and cultured for 3 and 20 weeks and compared them with data on their tissue of origin. We found that, besides the expected changes in short-term culture, the organoids showed profound changes in their epigenomes also during the long-term culture. The most prominent were epigenetic gene activation by H3K4me3 recruitment to previously unmodified genes and by H3K27me3 loss from originally bivalent genes. We showed that a long-term culture is linked to broad transcriptional changes that indicate an ongoing maturation and metabolic adaptation process. This process was disturbed in MMR-deficient mice, resulting in endoplasmic reticulum (ER) stress and Wnt activation. Our results can be explained in terms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed.
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- 2021
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7. How to Obtain a Mega-Intestine with Normal Morphology: In Silico Modelling of Postnatal Intestinal Growth in a Cd97-Transgenic Mouse
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Felix Hofmann, Torsten Thalheim, Karen Rother, Marianne Quaas, Christiane Kerner, Jens Przybilla, Gabriela Aust, and Joerg Galle
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mega-intestine ,postnatal development ,crypt formation ,Cd97 ,Klf4 ,Areg ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously with crypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing Cd97/Adgre5 in the intestinal epithelium develop a mega-intestine with normal microscopic morphology in adult mice. Here, we demonstrate premature intestinal differentiation in Cd97/Adgre5 transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, the growth of the intestinal epithelium becomes activated and its maturation suppressed. These changes are paralleled by postnatal regulation of growth factors and by an increased expression of secretory cell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforced tissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fate decisions during this period with the use of a 3D individual cell-based computer model. In the model, the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largely independent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly, the model suggests that, besides the growth activation of non-epithelial tissue layers, the formation of a mega-intestine requires a released growth control in the epithelium, enabling accelerated SC expansion. The similar intestinal morphology in Cd97/Adgre5 transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlled contact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine with normal microscopic morphology turns out to originate in changes of autonomous and conditional specification of the intestinal cell fate induced by the activation of Cd97/Adgre5.
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- 2021
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8. Fighting Against Promoter DNA Hyper-Methylation: Protective Histone Modification Profiles of Stress-Resistant Intestinal Stem Cells
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Torsten Thalheim, Lydia Hopp, Maria Herberg, Susann Siebert, Christiane Kerner, Marianne Quaas, Michal R. Schweiger, Gabriela Aust, and Joerg Galle
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promoter dna hyper-methylation ,histone methylation ,dna damage ,irradiation ,loss of msh2 function ,computational modeling ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Recently, we have suggested that promoter DNA hyper-methylation originates in DNA repair and that even successful DNA repair might confer this kind of epigenetic long-term change. Here, we ask for interrelations between promoter DNA methylation and histone modification changes observed in the intestine weeks after irradiation and/or following Msh2 loss. We focus on H3K4me3 recruitment to the promoter of H3K27me3 target genes. By RNA- and histone ChIP-sequencing, we demonstrate that this recruitment occurs without changes of the average gene transcription and does not involve H3K9me3. Applying a mathematical model of epigenetic regulation of transcription, we show that the recruitment can be explained by stronger DNA binding of H3K4me3 and H3K27me3 histone methyl-transferases as a consequence of lower DNA methylation. This scenario implicates stable transcription despite of H3K4me3 recruitment, in agreement with our RNA-seq data. Following several kinds of stress, including moderate irradiation, stress-sensitive intestinal stem cell (ISCs) are known to become replaced by more resistant populations. Our simulation results suggest that the stress-resistant ISCs are largely protected against promoter hyper-methylation of H3K27me3 target genes.
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- 2020
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9. p53 and cell cycle dependent transcription of kinesin family member 23 (KIF23) is controlled via a CHR promoter element bound by DREAM and MMB complexes.
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Martin Fischer, Inga Grundke, Sindy Sohr, Marianne Quaas, Saskia Hoffmann, Arne Knörck, Catalina Gumhold, and Karen Rother
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Medicine ,Science - Abstract
The microtubule-dependent molecular motor KIF23 (Kinesin family member 23) is one of two components of the centralspindlin complex assembled during late stages of mitosis. Formation of this complex is known as an essential step for cytokinesis. Here, we identified KIF23 as a new transcriptional target gene of the tumor suppressor protein p53. We showed that p53 reduces expression of KIF23 on the mRNA as well as the protein level in different cell types. Promoter reporter assays revealed that this repression results from downregulation of KIF23 promoter activity. CDK inhibitor p21(WAF1/CIP1) was shown to be necessary to mediate p53-dependent repression. Furthermore, we identified the highly conserved cell cycle genes homology region (CHR) in the KIF23 promoter to be strictly required for p53-dependent repression as well as for cell cycle-dependent expression of KIF23. Cell cycle- and p53-dependent regulation of KIF23 appeared to be controlled by differential binding of DREAM and MMB complexes to the CHR element. With this study, we describe a new mechanism for transcriptional regulation of KIF23. Considering the strongly supporting function of KIF23 in cytokinesis, its p53-dependent repression may contribute to the prevention of uncontrolled cell growth.
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- 2013
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10. Adhesion GPCR GPR56 Expression Profiling in Human Tissues
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Aust, Fyn Kaiser, Markus Morawski, Knut Krohn, Nada Rayes, Cheng-Chih Hsiao, Marianne Quaas, and Gabriela
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GPR56 ,ADGRG1 ,thyroid ,microglia - Abstract
Despite the immense functional relevance of GPR56 (gene ADGRG1) in highly diverse (patho)physiological processes such as tumorigenesis, immune regulation, and brain development, little is known about its exact tissue localization. Here, we validated antibodies for GPR56-specific binding using cells with tagged GPR56 or eliminated ADGRG1 in immunotechniques. Using the most suitable antibody, we then established the human GPR56 tissue expression profile. Overall, ADGRG1 RNA-sequencing data of human tissues and GPR56 protein expression correlate very well. In the adult brain especially, microglia are GPR56-positive. Outside the central nervous system, GPR56 is frequently expressed in cuboidal or highly prismatic secreting epithelia. High ADGRG1 mRNA, present in the thyroid, kidney, and placenta is related to elevated GPR56 in thyrocytes, kidney tubules, and the syncytiotrophoblast, respectively. GPR56 often appears in association with secreted proteins such as pepsinogen A in gastric chief cells and insulin in islet β-cells. In summary, GPR56 shows a broad, not cell-type restricted expression in humans.
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- 2021
- Full Text
- View/download PDF
11. Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine
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Gabriela Aust, Maria Herberg, Michal R. Schweiger, Michelle Hussong, Janine Altmüller, Marianne Quaas, Susann Siebert, Joerg Galle, Christiane Kerner, Karen Rother, and Torsten Thalheim
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0301 basic medicine ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,lcsh:QH426-470 ,DNA repair ,lcsh:Medicine ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,Histone H3 ,Mice ,0302 clinical medicine ,Histone methylation ,Intestinal Neoplasms ,Genetics ,Animals ,Humans ,Gene Regulatory Networks ,Epigenetics ,Molecular Biology ,Genetics (clinical) ,Aged ,Radiation ,biology ,Whole Genome Sequencing ,Research ,lcsh:R ,Methylation ,digestive system diseases ,Intestine ,Msh2 ,Intestines ,lcsh:Genetics ,Disease Models, Animal ,030104 developmental biology ,Histone ,MutS Homolog 2 Protein ,030220 oncology & carcinogenesis ,Case-Control Studies ,biology.protein ,Cancer research ,H3K4me3 ,Chromatin Immunoprecipitation Sequencing ,DNA mismatch repair ,Female ,Histone H3 methylation ,Technology Platforms ,Mismatch repair deficiency ,Developmental Biology - Abstract
Background Mismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we quantified genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2LoxP/LoxP (Msh2−/−) mice months before tumor onset. Results Histone H3 methylation increases in Msh2−/− compared to control Msh2+/+ mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2+/+ mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2+/+ mice 4 weeks after a single-radiation hit, whereas radiation of Msh2−/− mice left their histone methylation profiles almost unchanged. Conclusions MMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage. Electronic supplementary material The online version of this article (10.1186/s13148-019-0639-8) contains supplementary material, which is available to authorized users.
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- 2018
12. Mechano-Dependent Phosphorylation of the PDZ-Binding Motif of CD97/ADGRE5 Modulates Cellular Detachment
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Doreen Sittig, Marianne Quaas, Doris Hilbig, Ines Liebscher, Liane Seiler, Josef A. Käs, Enrico Warmt, Lawrence Banks, Gabriela Aust, Sven Rothemund, Ngoc Anh Hoang, Franz Hoffmann, and Julia Stürmer
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0301 basic medicine ,Scaffold protein ,biology ,Chemistry ,PDZ domain ,PDZ Domains ,macromolecular substances ,Actin cytoskeleton ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Receptors, G-Protein-Coupled ,Adherens junction ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Antigens, CD ,DLG1 ,biology.protein ,Phosphorylation ,Humans ,Mechanotransduction ,Cytoskeleton ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Cells respond to mechanical stimuli with altered signaling networks. Here, we show that mechanical forces rapidly induce phosphorylation of CD97/ADGRE5 (pCD97) at its intracellular C-terminal PDZ-binding motif (PBM). Biochemically, this phosphorylation disrupts CD97 binding to PDZ domains of the scaffold protein DLG1. In shear-stressed cells, pCD97 appears not only in junctions, retracting fibers, and the attachment area but also in lost membrane patches, demonstrating (intra)cellular detachment at the CD97 PBM. This motif is critical for the CD97-dependent mechanoresponse. Cells expressing CD97 without the PBM are more deformable, and under shear stress, these cells lose cell contacts faster and show changes in the actin cytoskeleton when compared with cells expressing full-length CD97. Our data indicate CD97 linkage to the cytoskeleton. Consistently, CD97 knockout phenocopies CD97 without the PBM, and membranous CD97 is organized in an F-actin-dependent manner. In summary, CD97 shapes the cellular mechanoresponse through signaling modulation via its PBM.
- Published
- 2017
13. p53 can repress transcription of cell cycle genes through a p21WAF1/CIP1-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements
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Gerd A. Müller, Marianne Quaas, and Kurt Engeland
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Cyclin-Dependent Kinase Inhibitor p21 ,p53 ,B-Myb ,Repressor ,Biology ,Protein complex binding ,Mice ,Cell Cycle News & Views ,Animals ,Humans ,DREAM complex ,Cyclin B2 ,E2F ,Molecular Biology ,E2F4 ,p130 ,G2 arrest ,p21 ,Cell Cycle ,Kv Channel-Interacting Proteins ,Promoter ,Cell Biology ,MuvB ,Cell cycle ,HCT116 Cells ,Molecular biology ,Cell Cycle Gene ,Repressor Proteins ,pRb ,Doxorubicin ,NIH 3T3 Cells ,DNA damage ,Tumor Suppressor Protein p53 ,MMB/DREAM ,repression ,Protein Binding ,Developmental Biology - Abstract
The tumor suppressor p53 plays an important role in cell cycle arrest by downregulating transcription. Many genes repressed by p53 code for proteins with functions in G₂/M. A large portion of these genes is controlled by cell cycle-dependent elements (CDE) and cell cycle genes homology regions (CHR) in their promoters. Cyclin B2 is an example of such a gene, with a function at the transition from G₂ to mitosis. We find that p53-dependent downregulation of cyclin B2 promoter activity is dependent on an intact CHR element. In the presence of high levels of p53 or p21(WAF1/CIP1), protein binding to the CHR switches from MMB to DREAM complex by shifting MuvB core-associated proteins from B-Myb to E2F4/DP1/p130. The results suggest a model for p53-dependent transcriptional repression by which p53 directly activates p21(WAF1/CIP1). The inhibitor then prevents further phosphorylation of p130 by cyclin-dependent kinases. The presence of hypophosphorylated pocket proteins shifts the equilibrium for complex formation from MMB to DREAM. In the case of promoters that do not hold CDE or E2F elements, binding of DREAM and MMB solely relies on a CHR site. Thus, p53 can repress target genes indirectly through CHR elements.
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- 2012
14. The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes
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Martin, Fischer, Marianne, Quaas, Lydia, Steiner, and Kurt, Engeland
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Cyclin-Dependent Kinase Inhibitor p21 ,Binding Sites ,Gene regulation, Chromatin and Epigenetics ,Mitosis ,Kv Channel-Interacting Proteins ,Response Elements ,G2 Phase Cell Cycle Checkpoints ,Repressor Proteins ,Mice ,Gene Expression Regulation ,Cell Line, Tumor ,Animals ,Humans ,Tumor Suppressor Protein p53 ,Promoter Regions, Genetic ,Protein Binding ,Signal Transduction - Abstract
The tumor suppressor p53 functions predominantly as a transcription factor by activating and downregulating gene expression, leading to cell cycle arrest or apoptosis. p53 was shown to indirectly repress transcription of the CCNB2, KIF23 and PLK4 cell cycle genes through the recently discovered p53-p21-DREAM-CDE/CHR pathway. However, it remained unclear whether this pathway is commonly used. Here, we identify genes regulated by p53 through this pathway in a genome-wide computational approach. The bioinformatic analysis is based on genome-wide DREAM complex binding data, p53-depedent mRNA expression data and a genome-wide definition of phylogenetically conserved CHR promoter elements. We find 210 target genes that are expected to be regulated by the p53-p21-DREAM-CDE/CHR pathway. The target gene list was verified by detailed analysis of p53-dependent repression of the cell cycle genes B-MYB (MYBL2), BUB1, CCNA2, CCNB1, CHEK2, MELK, POLD1, RAD18 and RAD54L. Most of the 210 target genes are essential regulators of G2 phase and mitosis. Thus, downregulation of these genes through the p53-p21-DREAM-CDE/CHR pathway appears to be a principal mechanism for G2/M cell cycle arrest by p53.
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- 2015
15. Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control
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Karen A. O'Hanlon, Baptiste Rolland, Juri Rappsilber, Arne Nedergaard Kousholt, Kurt Engeland, Ditte Kjærsgaard Klein, Heike I. Rösner, Johanna K. Ahlskog, Tobias Menzel, Marianne Quaas, Jens Vilstrup Johansen, Brian D Larsen, Michael Lees, Saskia Hoffmann, Claus Storgaard Sørensen, and David Walter
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Cell cycle checkpoint ,Cyclin E ,DNA Repair ,Cyclin D ,Cyclin A ,Immunoblotting ,Cyclin B ,General Physics and Astronomy ,Fluorescent Antibody Technique ,Cell Cycle Proteins ,General Biochemistry, Genetics and Molecular Biology ,Cell Line, Tumor ,Cyclins ,Humans ,Immunoprecipitation ,CHEK1 ,RNA, Small Interfering ,Luciferases ,DNA Primers ,Multidisciplinary ,biology ,Chemistry ,Ubiquitination ,General Chemistry ,Cell Cycle Checkpoints ,G2-M DNA damage checkpoint ,Flow Cytometry ,Cell biology ,HEK293 Cells ,biology.protein ,Mutagenesis, Site-Directed ,Trans-Activators ,RNA Interference ,Cyclin A2 - Abstract
Cells respond to DNA damage by activating cell cycle checkpoints to delay proliferation and facilitate DNA repair. Here, to uncover new checkpoint regulators, we perform RNA interference screening targeting genes involved in ubiquitylation processes. We show that the F-box protein cyclin F plays an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein cyclin F with suppression of the B-Myb/cyclin A pathway to ensure a DNA damage-induced checkpoint response in G2.
- Published
- 2014
16. Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein
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Gerd A. Müller, Axel Wintsche, Marianne Quaas, Martin Fischer, and Kurt Engeland
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Cyclin-Dependent Kinase Inhibitor p21 ,Transcriptional Activation ,Papillomavirus E7 Proteins ,Molecular Sequence Data ,Down-Regulation ,Cell Cycle Proteins ,Polo-like kinase ,Biology ,Protein Serine-Threonine Kinases ,Gene Regulation, Chromatin and Epigenetics ,Response Elements ,Cell Line ,Mice ,Genetics ,Transcriptional regulation ,Animals ,Humans ,Cell Cycle Protein ,Promoter Regions, Genetic ,E2F4 ,Mitosis ,Binding Sites ,Base Sequence ,Nuclear Respiratory Factor 1 ,Cell Cycle ,Promoter ,Cell cycle ,Molecular biology ,Cell Cycle Gene ,Repressor Proteins ,NIH 3T3 Cells ,Trans-Activators ,Tumor Suppressor Protein p53 - Abstract
Infection by oncogenic viruses is a frequent cause for tumor formation as observed in cervical cancer. Viral oncoproteins cause inactivation of p53 function and false transcriptional regulation of central cell cycle genes. Here we analyze the regulation of Plk4, serving as an example of many cell cycle- and p53-regulated genes. Cell cycle genes are often repressed via CDE and CHR elements in their promoters and activated by NF-Y binding to CCAAT-boxes. In contrast, general activation of Plk4 depends on NRF1 and CRE sites. Bioinformatic analyses imply that NRF1 and CRE are central elements of the transcriptional network controlling cell cycle genes. We identify CDE and CHR sites in the Plk4 promoter, which are necessary for binding of the DREAM (DP, RB-like, E2F4 and MuvB) complex and for mediating repression in G0/G1. When cells progress to G2 and mitosis, DREAM is replaced by the MMB (Myb-MuvB) complex that only requires the CHR element for binding. Plk4 expression is downregulated by the p53-p21(WAF1/CIP1)-DREAM signaling pathway through the CDE and CHR sites. Cell cycle- and p53-dependent repression is abrogated by HPV E7 oncoprotein. Together with genome-wide analyses our results imply that many cell cycle genes upregulated in tumors by viral infection are bound by DREAM through CDE/CHR sites.
- Published
- 2013
17. p53 and Cell Cycle Dependent Transcription of kinesin family member 23 (KIF23) Is Controlled Via a CHR Promoter Element Bound by DREAM and MMB Complexes
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Karen Rother, Sindy Sohr, Marianne Quaas, Arne Knörck, Saskia Hoffmann, Catalina Gumhold, Inga Grundke, and Martin Fischer
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Transcription, Genetic ,KIF23 ,Mice ,Molecular cell biology ,Basic Cancer Research ,Protein Isoforms ,Promoter Regions, Genetic ,Multidisciplinary ,Protein Stability ,Cell Cycle ,Kv Channel-Interacting Proteins ,Cell cycle ,Cell Cycle Gene ,Oncology ,Kinesin ,Medicine ,Microtubule-Associated Proteins ,Cell Division ,Research Article ,Protein Binding ,Cyclin-Dependent Kinase Inhibitor p21 ,Science ,DNA transcription ,Biology ,Response Elements ,Molecular Genetics ,Genetics ,Human Cloning ,Animals ,Humans ,Gene Regulation ,Gene Silencing ,RNA, Messenger ,Psychological repression ,Mitosis ,Cytokinesis ,Centralspindlin complex ,HCT116 Cells ,Molecular biology ,Oncogene Proteins v-myb ,Repressor Proteins ,Gene Expression Regulation ,NIH 3T3 Cells ,Gene expression ,Tumor Suppressor Protein p53 ,Cloning - Abstract
The microtubule-dependent molecular motor KIF23 (Kinesin family member 23) is one of two components of the centralspindlin complex assembled during late stages of mitosis. Formation of this complex is known as an essential step for cytokinesis. Here, we identified KIF23 as a new transcriptional target gene of the tumor suppressor protein p53. We showed that p53 reduces expression of KIF23 on the mRNA as well as the protein level in different cell types. Promoter reporter assays revealed that this repression results from downregulation of KIF23 promoter activity. CDK inhibitor p21(WAF1/CIP1) was shown to be necessary to mediate p53-dependent repression. Furthermore, we identified the highly conserved cell cycle genes homology region (CHR) in the KIF23 promoter to be strictly required for p53-dependent repression as well as for cell cycle-dependent expression of KIF23. Cell cycle- and p53-dependent regulation of KIF23 appeared to be controlled by differential binding of DREAM and MMB complexes to the CHR element. With this study, we describe a new mechanism for transcriptional regulation of KIF23. Considering the strongly supporting function of KIF23 in cytokinesis, its p53-dependent repression may contribute to the prevention of uncontrolled cell growth.
- Published
- 2013
18. The forkhead transcription factor FOXM1 controls cell cycle-dependent gene expression through an atypical chromatin binding mechanism
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Andrew D. Sharrocks, Kurt Engeland, Martin Fischer, Gerd A. Müller, Benjamin Stutchbury, Xi Chen, Namshik Han, and Marianne Quaas
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Chromatin Immunoprecipitation ,Mitosis ,Biology ,Mice ,Cell Line, Tumor ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Cloning, Molecular ,Phosphorylation ,FOXD3 ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,ChIA-PET ,Genetics ,Reverse Transcriptase Polymerase Chain Reaction ,Chromatin binding ,Pioneer factor ,Cell Cycle ,Forkhead Box Protein M1 ,Computational Biology ,Forkhead Transcription Factors ,Cell Biology ,Articles ,HCT116 Cells ,Chromatin ,ChIP-sequencing ,DNA-Binding Proteins ,Genes, cdc ,HEK293 Cells ,Gene Expression Regulation ,NIH 3T3 Cells ,FOXA2 ,Cell Division ,Protein Binding - Abstract
There are nearly 50 forkhead (FOX) transcription factors encoded in the human genome and, due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here, we used chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G(2) and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR (cell cycle genes homology region) elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor that allows it to specifically control cell cycle-dependent gene expression.
- Published
- 2012
19. The CHR promoter element controls cell cycle-dependent gene transcription and binds the DREAM and MMB complexes
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Eberhard Krause, Martin Fischer, Megha Padi, Michael Schümann, Gerd A. Müller, Marianne Quaas, Larisa Litovchick, Kurt Engeland, and James A. DeCaprio
- Subjects
Transcriptional Activation ,Transcription, Genetic ,Gene Regulation, Chromatin and Epigenetics ,Biology ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Transcriptional regulation ,Animals ,Humans ,DREAM complex ,Cyclin B2 ,Promoter Regions, Genetic ,Transcription factor ,E2F4 ,Conserved Sequence ,Phylogeny ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Cyclin-dependent kinase 1 ,Binding Sites ,Base Sequence ,Promoter ,Molecular biology ,Cell Cycle Gene ,Genes, cdc ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Ubiquitin-Conjugating Enzymes ,NIH 3T3 Cells ,Transcription Factors - Abstract
Cell cycle-dependent gene expression is often controlled on the transcriptional level. Genes like cyclin B, CDC2 and CDC25C are regulated by cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR) promoter elements mainly through repression in G(0)/G(1). It had been suggested that E2F4 binding to CDE sites is central to transcriptional regulation. However, some promoters are only controlled by a CHR. We identify the DREAM complex binding to the CHR of mouse and human cyclin B2 promoters in G(0). Association of DREAM and cell cycle-dependent regulation is abrogated when the CHR is mutated. Although E2f4 is part of the complex, a CDE is not essential but can enhance binding of DREAM. We show that the CHR element is not only necessary for repression of gene transcription in G(0)/G(1), but also for activation in S, G(2) and M phases. In proliferating cells, the B-myb-containing MMB complex binds the CHR of both promoters independently of the CDE. Bioinformatic analyses identify many genes which contain conserved CHR elements in promoters binding the DREAM complex. With Ube2c as an example from that screen, we show that inverse CHR sites are functional promoter elements that can bind DREAM and MMB. Our findings indicate that the CHR is central to DREAM/MMB-dependent transcriptional control during the cell cycle.
- Published
- 2011
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