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Article ; Online: The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas.

Sánchez-Tilló, Ester / Pedrosa, Leire / Vila, Ingrid / Chen, Yongxu / Győrffy, Balázs / Sánchez-Moral, Lidia / Siles, Laura / Lozano, Juan J / Esteve-Codina, Anna / Darling, Douglas S / Cuatrecasas, Miriam / Castells, Antoni / Maurel, Joan / Postigo, Antonio

JCI insight

2023 Volume 8, Issue 20

Abstract: Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. ... ...

Abstract	Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
MeSH term(s)	Animals ; Humans ; Mice ; Carcinoma ; Colorectal Neoplasms/pathology ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction ; Zinc Finger E-box-Binding Homeobox 1/genetics ; Zinc Finger E-box-Binding Homeobox 1/metabolism
Chemical Substances	BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ZEB1 protein, human ; Zinc Finger E-box-Binding Homeobox 1
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.164629
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Article ; Online: Regulation of muscle atrophy-related genes by the opposing transcriptional activities of ZEB1/CtBP and FOXO3.

Ninfali, Chiara / Siles, Laura / Darling, Douglas S / Postigo, Antonio

Nucleic acids research

2018 Volume 46, Issue 20, Page(s) 10697–10708

Abstract: Multiple physiopathological and clinical conditions trigger skeletal muscle atrophy through the induction of a group of proteins (atrogenes) that includes components of the ubiquitin-proteasome and autophagy-lysosomal systems. Atrogenes are induced by ... ...

Abstract	Multiple physiopathological and clinical conditions trigger skeletal muscle atrophy through the induction of a group of proteins (atrogenes) that includes components of the ubiquitin-proteasome and autophagy-lysosomal systems. Atrogenes are induced by FOXO transcription factors, but their regulation is still not fully understood. Here, we showed that the transcription factor ZEB1, best known for promoting tumor progression, inhibits muscle atrophy and atrogene expression by antagonizing FOXO3-mediated induction of atrogenes. Compared to wild-type counterparts, hindlimb immobilization in Zeb1-deficient mice resulted in enhanced muscle atrophy and higher expression of a number of atrogenes, including Atrogin-1/Fbxo32, MuRF1/Trim63, Ctsl, 4ebp1, Gabarapl1, Psma1 and Nrf2. Likewise, in the C2C12 myogenic cell model, ZEB1 knockdown augmented both myotube diameter reduction and atrogene upregulation in response to nutrient deprivation. Mechanistically, ZEB1 directly represses in vitro and in vivo Fbxo32 and Trim63 promoter transcription in a stage-dependent manner and in a reverse pattern with MYOD1. ZEB1 bound to the Fbxo32 promoter in undifferentiated myoblasts and atrophic myotubes, but not in non-atrophic myotubes, where it is displaced by MYOD1. ZEB1 repressed both promoters through CtBP-mediated inhibition of FOXO3 transcriptional activity. These results set ZEB1 as a new target in therapeutic approaches to clinical conditions causing muscle mass loss.
MeSH term(s)	Alcohol Oxidoreductases/genetics ; Alcohol Oxidoreductases/metabolism ; Animals ; Cell Differentiation ; Cell Line ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Forkhead Box Protein O3/genetics ; Forkhead Box Protein O3/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Homeostasis ; Humans ; Mice ; Mice, Transgenic ; Muscle Fibers, Skeletal/metabolism ; Muscle Proteins/metabolism ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/genetics ; Muscular Atrophy/metabolism ; Myoblasts/metabolism ; Neoplasms/metabolism ; Promoter Regions, Genetic ; SKP Cullin F-Box Protein Ligases/metabolism ; Transcription, Genetic ; Zinc Finger E-box-Binding Homeobox 1/genetics ; Zinc Finger E-box-Binding Homeobox 1/metabolism
Chemical Substances	DNA-Binding Proteins ; FOXO3 protein, human ; Forkhead Box Protein O3 ; FoxO3 protein, mouse ; Muscle Proteins ; ZEB1 protein, human ; ZEB1 protein, mouse ; Zinc Finger E-box-Binding Homeobox 1 ; Alcohol Oxidoreductases (EC 1.1.-) ; C-terminal binding protein (EC 1.1.1.-) ; FBXO32 protein, human (EC 2.3.2.27) ; Fbxo32 protein, mouse (EC 2.3.2.27) ; SKP Cullin F-Box Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2018-12-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gky835
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Zs.A 1067: Show issues

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Article ; Online: ZEB1 protects skeletal muscle from damage and is required for its regeneration.

Siles, Laura / Ninfali, Chiara / Cortés, Marlies / Darling, Douglas S / Postigo, Antonio

Nature communications

2019 Volume 10, Issue 1, Page(s) 1364

Abstract: The mechanisms linking muscle injury and regeneration are not fully understood. Here we report an unexpected role for ZEB1 regulating inflammatory and repair responses in dystrophic and acutely injured muscles. ZEB1 is upregulated in the undamaged and ... ...

Abstract	The mechanisms linking muscle injury and regeneration are not fully understood. Here we report an unexpected role for ZEB1 regulating inflammatory and repair responses in dystrophic and acutely injured muscles. ZEB1 is upregulated in the undamaged and regenerating myofibers of injured muscles. Compared to wild-type counterparts, Zeb1-deficient injured muscles exhibit enhanced damage that corresponds with a retarded p38-MAPK-dependent transition of their macrophages towards an anti-inflammatory phenotype. Zeb1-deficient injured muscles also display a delayed and poorer regeneration that is accounted by the retarded anti-inflammatory macrophage transition and their intrinsically deficient muscle satellite cells (MuSCs). Macrophages in Zeb1-deficient injured muscles show lower phosphorylation of p38 and its forced activation reverts the enhanced muscle damage and poorer regeneration. MuSCs require ZEB1 to maintain their quiescence, prevent their premature activation following injury, and drive efficient regeneration in dystrophic muscles. These data indicate that ZEB1 protects muscle from damage and is required for its regeneration.
MeSH term(s)	Animals ; Chemokine CCL2/genetics ; Chemokine CCL2/immunology ; Chromones/pharmacology ; Disease Models, Animal ; Flavonoids/pharmacology ; Gene Expression Regulation ; Humans ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor I/immunology ; Laminin/genetics ; Laminin/immunology ; Macrophages/immunology ; Macrophages/pathology ; Mice ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 1/immunology ; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3/genetics ; Mitogen-Activated Protein Kinase 3/immunology ; Morpholines/pharmacology ; Muscle, Skeletal/immunology ; Muscle, Skeletal/injuries ; Muscle, Skeletal/metabolism ; Muscular Dystrophies/genetics ; Muscular Dystrophies/immunology ; Muscular Dystrophies/pathology ; Phenotype ; Phosphorylation ; RNA, Messenger/genetics ; RNA, Messenger/immunology ; Regeneration/genetics ; Regeneration/immunology ; Satellite Cells, Skeletal Muscle/immunology ; Satellite Cells, Skeletal Muscle/metabolism ; Satellite Cells, Skeletal Muscle/pathology ; Signal Transduction ; Zinc Finger E-box-Binding Homeobox 1/deficiency ; Zinc Finger E-box-Binding Homeobox 1/genetics ; Zinc Finger E-box-Binding Homeobox 1/immunology ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/immunology
Chemical Substances	Ccl2 protein, mouse ; Chemokine CCL2 ; Chromones ; Flavonoids ; Laminin ; Morpholines ; RNA, Messenger ; ZEB1 protein, mouse ; Zinc Finger E-box-Binding Homeobox 1 ; insulin-like growth factor-1, mouse ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; Insulin-Like Growth Factor I (67763-96-6) ; Mapk1 protein, mouse (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (SJE1IO5E3I)
Language	English
Publishing date	2019-03-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-08983-8
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Article: Use of multiple time points to model parotid differentiation.

Metzler, Melissa A / Appana, Savitri / Brock, Guy N / Darling, Douglas S

Genomics data

2015 Volume 5, Page(s) 82–88

Abstract: In order to understand the process of terminal differentiation in salivary acinar cells, mRNA and microRNA expression was measured across the month long process of differentiation in the parotid gland of the rat. Acinar cells were isolated at either nine ...

Abstract	In order to understand the process of terminal differentiation in salivary acinar cells, mRNA and microRNA expression was measured across the month long process of differentiation in the parotid gland of the rat. Acinar cells were isolated at either nine time points (mRNA) or four time points (microRNA) in triplicate using laser capture microdissection (LCM). One of the values of this dataset comes from the high quality RNA (RIN > 7) that was used in this study, which can be prohibitively difficult to obtain from such an RNaseI-rich tissue. Global mRNA expression was measured by rat genome microarray hybridization (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65586), and expression of microRNAs by qPCR array (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65324). Comparing expression at different ages, 2656 mRNAs and 64 microRNAs were identified as differentially expressed. Because mRNA expression was sampled at many time points, clustering and regression analysis were able to identify dynamic expression patterns that had not been implicated in acinar differentiation before. Integration of the two datasets allowed the identification of microRNA target genes, and a gene regulatory network. Bioinformatics R code and additional details of experimental methods and data analysis are provided.
Language	English
Publishing date	2015-05-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2751131-5
ISSN	2213-5960
ISSN	2213-5960
DOI	10.1016/j.gdata.2015.05.005
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Article: Use of multiple time points to model parotid differentiation

Metzler, Melissa A / Appana, Savitri / Brock, Guy N / Darling, Douglas S

Genomics Data. 2015 Sept., v. 5

2015

Abstract	In order to understand the process of terminal differentiation in salivary acinar cells, mRNA and microRNA expression was measured across the month long process of differentiation in the parotid gland of the rat. Acinar cells were isolated at either nine time points (mRNA) or four time points (microRNA) in triplicate using laser capture microdissection (LCM). One of the values of this dataset comes from the high quality RNA (RIN>7) that was used in this study, which can be prohibitively difficult to obtain from such an RNaseI-rich tissue. Global mRNA expression was measured by rat genome microarray hybridization (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65586), and expression of microRNAs by qPCR array (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65324). Comparing expression at different ages, 2656 mRNAs and 64 microRNAs were identified as differentially expressed. Because mRNA expression was sampled at many time points, clustering and regression analysis were able to identify dynamic expression patterns that had not been implicated in acinar differentiation before. Integration of the two datasets allowed the identification of microRNA target genes, and a gene regulatory network. Bioinformatics R code and additional details of experimental methods and data analysis are provided.
Keywords	acinar cells ; bioinformatics ; data collection ; gene expression ; gene expression regulation ; gene regulatory networks ; genome ; messenger RNA ; microRNA ; microarray technology ; models ; parotid gland ; quantitative polymerase chain reaction ; rats ; regression analysis
Language	English
Dates of publication	2015-09
Size	p. 82-88.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2751131-5
ISSN	2213-5960
ISSN	2213-5960
DOI	10.1016/j.gdata.2015.05.005
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Article ; Online: Phosphorylation Regulates Functions of ZEB1 Transcription Factor.

Llorens, M Candelaria / Lorenzatti, Guadalupe / Cavallo, Natalia L / Vaglienti, Maria V / Perrone, Ana P / Carenbauer, Anne L / Darling, Douglas S / Cabanillas, Ana M

Journal of cellular physiology

2016 Volume 231, Issue 10, Page(s) 2205–2217

Abstract: ZEB1 transcription factor is important in both development and disease, including many TGFβ-induced responses, and the epithelial-to-mesenchymal transition (EMT) by which many tumors undergo metastasis. ZEB1 is differentially phosphorylated in different ... ...

Abstract	ZEB1 transcription factor is important in both development and disease, including many TGFβ-induced responses, and the epithelial-to-mesenchymal transition (EMT) by which many tumors undergo metastasis. ZEB1 is differentially phosphorylated in different cell types; however the role of phosphorylation in ZEB1 activity is unknown. Luciferase reporter studies and electrophoresis mobility shift assays (EMSA) show that a decrease in phosphorylation of ZEB1 increases both DNA-binding and transcriptional repression of ZEB1 target genes. Functional analysis of ZEB1 phosphorylation site mutants near the second zinc finger domain (termed ZD2) show that increased phosphorylation (due to either PMA plus ionomycin, or IGF-1) can inhibit transcriptional repression by either a ZEB1-ZD2 domain clone, or full-length ZEB1. This approach identifies phosphosites that have a substantial effect regulating the transcriptional and DNA-binding activity of ZEB1. Immunoprecipitation with anti-ZEB1 antibodies followed by western analysis with a phospho-Threonine-Proline-specific antibody indicates that the ERK consensus site at Thr-867 is phosphorylated in ZEB1. In addition to disrupting in vitro DNA-binding measured by EMSA, IGF-1-induced MEK/ERK phosphorylation is sufficient to disrupt nuclear localization of GFP-ZEB1 fusion clones. These data suggest that phosphorylation of ZEB1 integrates TGFβ signaling with other signaling pathways such as IGF-1. J. Cell. Physiol. 231: 2205-2217, 2016. © 2016 Wiley Periodicals, Inc.
MeSH term(s)	Animals ; CHO Cells ; Cricetulus ; Epithelial-Mesenchymal Transition ; Insulin-Like Growth Factor I/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Phosphorylation ; Signal Transduction/physiology ; Zinc Finger E-box-Binding Homeobox 1/genetics ; Zinc Finger E-box-Binding Homeobox 1/metabolism ; Zinc Fingers
Chemical Substances	Zinc Finger E-box-Binding Homeobox 1 ; Insulin-Like Growth Factor I (67763-96-6) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2016-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.25338
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Uc I Zs.212: Show issues

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Article: Combination of a zinc finger and homeodomain required for protein-interaction.

Smith, Gregory E / Darling, Douglas S

Molecular biology reports

2003 Volume 30, Issue 4, Page(s) 199–206

Abstract: The Zinc Finger Homeodomain Enhancer-binding Protein (Zfhep) is involved in skeletal patterning, immune cell, muscle, and brain development, and is necessary for life. Zfhep contains a single central homeodomain (HD) adjacent to an isolated zinc finger, ... ...

Abstract	The Zinc Finger Homeodomain Enhancer-binding Protein (Zfhep) is involved in skeletal patterning, immune cell, muscle, and brain development, and is necessary for life. Zfhep contains a single central homeodomain (HD) adjacent to an isolated zinc finger, the function of which is unknown. The placement of a zinc finger so close to a homeodomain is novel in nature. The aim of this work was to characterize the Zfhep homeodomain (HD) or the zinc finger homeodomain (ZHD), with respect to DNA-binding and protein-protein interactions. Glutathione-S-transferase (GST) fusion proteins containing either just the HD or both the zinc finger and HD (ZHD) were expressed in E. coli. The GST fusion protein affinity-binding assay demonstrated that Zfhep ZHD interacts specifically with the POU domain of the Oct-1 transcription factor. The adjacent zinc finger is required since Zfhep HD alone does not interact with Oct-1 POU domain. Furthermore, ZHD does not bind to the POU homeodomain lacking the POU specific region. These results demonstrate that the Zfhep zinc finger homeodomain motif functions as a protein-binding domain in vitro, and suggests that Zfhep may modulate the activity of POU domain transcription factors. However, neither the Zfhep ZHD nor the HD bound DNA in EMSA or selected a DNA-binding site from a pool of random oligonucleotides. This is the first demonstration of a function for the HD region of Zfhep, which is the first case of a bi-partite domain requiring both a zinc finger and a HD for binding to protein.
MeSH term(s)	Amino Acid Sequence ; Animals ; Binding Sites ; DNA-Binding Proteins/metabolism ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Host Cell Factor C1 ; Molecular Sequence Data ; Octamer Transcription Factor-1 ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Zinc Fingers
Chemical Substances	DNA-Binding Proteins ; Homeodomain Proteins ; Host Cell Factor C1 ; Octamer Transcription Factor-1 ; Pou2f1 protein, rat ; Recombinant Fusion Proteins ; Transcription Factors ; ZEB1 protein, rat
Language	English
Publishing date	2003-07-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	186544-4
ISSN	1573-4978 ; 0301-4851
ISSN (online)	1573-4978
ISSN	0301-4851
DOI	10.1023/a:1026330907065
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Zs.A 1140: Show issues

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Article ; Online: Model discrimination in dynamic molecular systems: application to parotid de-differentiation network.

Kim, Jaejik / Li, Jiaxu / Venkatesh, Srirangapatnam G / Darling, Douglas S / Rempala, Grzegorz A

Journal of computational biology : a journal of computational molecular cell biology

2013 Volume 20, Issue 7, Page(s) 524–539

Abstract: In modern systems biology the modeling of longitudinal data, such as changes in mRNA concentrations, is often of interest. Fully parametric, ordinary differential equations (ODE)-based models are typically developed for the purpose, but their lack of fit ...

Abstract	In modern systems biology the modeling of longitudinal data, such as changes in mRNA concentrations, is often of interest. Fully parametric, ordinary differential equations (ODE)-based models are typically developed for the purpose, but their lack of fit in some examples indicates that more flexible Bayesian models may be beneficial, particularly when there are relatively few data points available. However, under such sparse data scenarios it is often difficult to identify the most suitable model. The process of falsifying inappropriate candidate models is called model discrimination. We propose here a formal method of discrimination between competing Bayesian mixture-type longitudinal models that is both sensitive and sufficiently flexible to account for the complex variability of the longitudinal molecular data. The ideas from the field of Bayesian analysis of computer model validation are applied, along with modern Markov Chain Monte Carlo (MCMC) algorithms, in order to derive an appropriate Bayes discriminant rule. We restrict attention to the two-model comparison problem and present the application of the proposed rule to the mRNA data in the de-differentiation network of three mRNA concentrations in mammalian salivary glands as well as to a large synthetic dataset derived from the model used in the recent DREAM6 competition.
MeSH term(s)	Algorithms ; Amylases/genetics ; Amylases/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Bayes Theorem ; Humans ; Markov Chains ; Models, Statistical ; Molecular Dynamics Simulation ; Monte Carlo Method ; Parotid Gland/cytology ; Parotid Gland/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Salivary Proteins and Peptides/genetics ; Salivary Proteins and Peptides/metabolism ; Time Factors
Chemical Substances	BHLHA15 protein, human ; BPIFA2 protein, human ; Basic Helix-Loop-Helix Transcription Factors ; RNA, Messenger ; Salivary Proteins and Peptides ; Amylases (EC 3.2.1.-)
Language	English
Publishing date	2013-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2030900-4
ISSN	1557-8666 ; 1066-5277
ISSN (online)	1557-8666
ISSN	1066-5277
DOI	10.1089/cmb.2011.0222
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Article ; Online: ZEB1 Imposes a Temporary Stage-Dependent Inhibition of Muscle Gene Expression and Differentiation via CtBP-Mediated Transcriptional Repression

Siles, Laura / Sánchez-Tilló, Ester / Im, Chong-wŏn / Darling, Douglas S. / Kroll, Kristen L. / Postigo, Antonio

Molecular and Cellular Biology. 2013 Apr. 1, v. 33, no. 7 p.1368-1382

2013

Abstract: Skeletal muscle development is orchestrated by the myogenic regulatory factor MyoD, whose activity is blocked in myoblasts by proteins preventing its nuclear translocation and/or binding to G/C-centered E-boxes in target genes. Recent evidence indicates ... ...

Abstract	Skeletal muscle development is orchestrated by the myogenic regulatory factor MyoD, whose activity is blocked in myoblasts by proteins preventing its nuclear translocation and/or binding to G/C-centered E-boxes in target genes. Recent evidence indicates that muscle gene expression is also regulated at the cis level by differential affinity for DNA between MyoD and other E-box binding proteins during myogenesis. MyoD binds to G/C-centered E-boxes, enriched in muscle differentiation genes, in myotubes but not in myoblasts. Here, we used cell-based and in vivo Drosophila, Xenopus laevis, and mouse models to show that ZEB1, a G/C-centered E-box binding transcriptional repressor, imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression. We found that, contrary to MyoD, ZEB1 binds to G/C-centered E-boxes in muscle differentiation genes at the myoblast stage but not in myotubes. Its knockdown results in precocious expression of muscle differentiation genes and acceleration of myotube formation. Inhibition of muscle genes by ZEB1 occurs via transcriptional repression and involves recruitment of the CtBP corepressor. Lastly, we show that the pattern of gene expression associated with muscle differentiation is accelerated in ZEB1 ⁻/⁻ mouse embryos. These results set ZEB1 as an important regulator of the temporal pattern of gene expression controlling muscle differentiation.
Keywords	DNA ; Drosophila ; Xenopus laevis ; gene expression ; mice ; muscle development ; muscles ; myoblasts ; myogenic regulatory factors ; myotubes ; repressor proteins ; skeletal muscle ; transcription (genetics)
Language	English
Dates of publication	2013-0401
Size	p. 1368-1382.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01259-12
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 1666: Show issues

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Article ; Online: ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells.

de Barrios, Oriol / Sanchez-Moral, Lidia / Cortés, Marlies / Ninfali, Chiara / Profitós-Pelejà, Nuria / Martínez-Campanario, M C / Siles, Laura / Del Campo, Rosa / Fernández-Aceñero, María Jesús / Darling, Douglas S / Castells, Antoni / Maurel, Joan / Salas, Azucena / Dean, Douglas C / Postigo, Antonio

Gut

2019 Volume 68, Issue 12, Page(s) 2129–2141

Abstract: Objective: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and ... ...

Abstract	Objective: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC. Design: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. Results: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Conclusions: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.
MeSH term(s)	Animals ; Biopsy ; Cells, Cultured ; Colitis, Ulcerative/complications ; Colitis, Ulcerative/genetics ; Colitis, Ulcerative/metabolism ; Colonic Neoplasms/etiology ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; DNA Glycosylases/genetics ; DNA Glycosylases/metabolism ; DNA Repair ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Gene Expression Regulation, Neoplastic ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms, Experimental ; RNA, Neoplasm/genetics ; Zinc Finger E-box-Binding Homeobox 1/genetics ; Zinc Finger E-box-Binding Homeobox 1/metabolism ; Zinc Fingers
Chemical Substances	RNA, Neoplasm ; ZEB1 protein, human ; Zinc Finger E-box-Binding Homeobox 1 ; DNA Glycosylases (EC 3.2.2.-) ; DNA-3-methyladenine glycosidase II (EC 3.2.2.21)
Language	English
Publishing date	2019-07-31
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2018-317294
Database	MEDical Literature Analysis and Retrieval System OnLINE

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