The Experts below are selected from a list of 1860 Experts worldwide ranked by ideXlab platform
Thomas Brabletz - One of the best experts on this subject based on the ideXlab platform.
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The Transcription Factor ZEB1 regulates stem cell self-renewal and astroglial fate in the adult hippocampus
2020Co-Authors: Bhavana Gupta, Thomas Brabletz, Simone Brabletz, Marc P. Stemmler, Adam C. Errington, Florian A. SiebzehnrublAbstract:Radial glia-like (RGL) cells persist in the adult mammalian hippocampus where they give rise to new neurons and astrocytes throughout life. Many studies have investigated the process of adult neurogenesis, but Factors deciding between neuronal and astroglial fate are incompletely understood. Here, we evaluate the functions of the Transcription Factor zinc finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells as well as for astroglial lineage specification. Genetic deletion of ZEB1 causes differentiation-coupled depletion of RGL cells resulting in an increase of newborn neurons at the expense of newly generated astrocytes. This is due to a shift towards symmetric cell divisions that consume the RGL cell and generate pro-neuronal progenies. We identify ZEB1 as a regulator of stem cell self-renewal and lineage specification in the adult hippocampus.
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EMT Transcription Factor ZEB1 alters the epigenetic landscape of colorectal cancer cells.
Cell death & disease, 2020Co-Authors: Pablo Lindner, Thomas Brabletz, Sushmita Paul, Markus Eckstein, Chuanpit Hampel, Julienne K. Muenzner, Katharina Erlenbach-wuensch, P Husayn Ahmed, Vijayalakshmi Mahadevan, Arndt HartmannAbstract:Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT Transcription Factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct Transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.
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Generation and characterization of mice for conditional inactivation of ZEB1
Genesis (New York N.Y. : 2000), 2017Co-Authors: Simone Brabletz, Thomas Brabletz, Angela M Krebs, Julia Mitschke, Maria Lasierra Losada, Otto Schmalhofer, Marc P. StemmlerAbstract:The multizinc finger containing Transcription Factor ZEB1 plays crucial roles during various aspects of mammalian development and tumorigenesis. Best studied in human tumors, ZEB1 is activating the embryo-derived program of epithelial-mesenchymal transition (EMT). The aberrant activation of EMT confers an invasive metastasizing phenotype with acquisition of stem cell properties and resistance to radio- and chemotherapy. Although ZEB1 has very important functions in tumor progression, not much is known about its role in physiological contexts and during development and homeostasis. We describe the generation of ZEB1flox/flox mice carrying a targeted mutation for conditional ZEB1 gene inactivation and show that homozygous ZEB1-depletion in the germline results in a phenotype similar to the conventional ZEB1 knockout.
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the Transcription Factor ZEB1 δef1 promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Oncogene, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, L Descovich, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Thomas Brabletz, Dennis Strand, P ObristAbstract:The Transcription Factor ZEB1 ( δ EF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
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The Transcription Factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Oncogene, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, L Descovich, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Thomas Brabletz, Dennis Strand, P ObristAbstract:Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of Transcription Factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified Transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo , and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro . In human colorectal cancer, ZEB1 expression was limited to the tumour–host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.
P Obrist - One of the best experts on this subject based on the ideXlab platform.
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the Transcription Factor ZEB1 δef1 promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Oncogene, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, L Descovich, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Thomas Brabletz, Dennis Strand, P ObristAbstract:The Transcription Factor ZEB1 ( δ EF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
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The Transcription Factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Oncogene, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, L Descovich, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Thomas Brabletz, Dennis Strand, P ObristAbstract:Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of Transcription Factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified Transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo , and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro . In human colorectal cancer, ZEB1 expression was limited to the tumour–host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.
Kirsten Aigner - One of the best experts on this subject based on the ideXlab platform.
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the Transcription Factor ZEB1 δef1 promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Oncogene, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, L Descovich, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Thomas Brabletz, Dennis Strand, P ObristAbstract:The Transcription Factor ZEB1 ( δ EF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
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The Transcription Factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Oncogene, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, L Descovich, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Thomas Brabletz, Dennis Strand, P ObristAbstract:Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of Transcription Factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified Transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo , and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro . In human colorectal cancer, ZEB1 expression was limited to the tumour–host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.
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The Transcription Factor ZEB1 (δEF1) represses Plakophilin 3 during human cancer progression
FEBS letters, 2007Co-Authors: Kirsten Aigner, Brigitta Dampier, Mario Mikula, Aneesa Sultan, Martin Schreiber, Wolfgang Mikulits, Luise Descovich, Stefan Bonné, Frans Van Roy, Thomas BrabletzAbstract:Plakophilin 3 (PKP3) belongs to the p120ctn family of armadillo-related proteins predominantly functioning in desmosome formation. Here we report that PKP3 is Transcriptionally repressed by the E-cadherin repressor ZEB1 in metastatic cancer cells. ZEB1 physically associates with two conserved E-box elements in the PKP3 promoter and partially represses the activity of corresponding human and mouse PKP3 promoter fragments in reporter gene assays. In human tumours ZEB1 is upregulated in invasive cancer cells at the tumour–host interface, which is accompanied by downregulation of PKP3 expression levels. Hence, the Transcriptional repression of PKP3 by ZEB1 contributes to ZEB1-mediated disintegration of intercellular adhesion and epithelial to mesenchymal transition.
Antonio Postigo - One of the best experts on this subject based on the ideXlab platform.
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Regulation of muscle atrophy-related genes by the opposing Transcriptional activities of ZEB1/CtBP and FOXO3
Nucleic acids research, 2018Co-Authors: Chiara Ninfali, Douglas S. Darling, Laura Siles, Antonio PostigoAbstract: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.
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the ZEB1 Transcription Factor acts in a negative feedback loop with mir200 downstream of ras and rb1 to regulate bmi1 expression
Journal of Biological Chemistry, 2014Co-Authors: Ester Sancheztillo, Li Huang, Sucheta Telang, Miriam Cuatrecasas, Xiaoqin Lu, Brian Clem, A B Jenson, Jason Chesney, Antonio PostigoAbstract:Ras mutations are frequent in cancer cells where they drive proliferation and resistance to apoptosis. However in primary cells, mutant Ras instead can cause oncogene-induced senescence, a tumor suppressor function linked to repression of the polycomb Factor Bmi1, which normally regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki). It is unclear how Ras causes repression of Bmi1 in primary cells to suppress tumor formation while inducing the gene in cancer cells to drive tumor progression. Ras also induces the EMT Transcription Factor ZEB1 to trigger tumor invasion and metastasis. Beyond its well-documented role in EMT, ZEB1 is important for maintaining repression of cdki. Indeed, heterozygous mutation of ZEB1 is sufficient for elevated cdki expression, leading to premature senescence of primary cells. A similar phenotype is evident with Bmi1 mutation. We show that activation of Rb1 in response to mutant Ras causes dominant repression of ZEB1 in primary cells, but loss of the Rb1 pathway is a hallmark of cancer cells and in the absence of such Rb1 repression Ras induces ZEB1 in cancer cells. ZEB1 represses miR-200 in the context of a mutual repression loop. Because miR-200 represses Bmi1, induction of ZEB1 leads to induction of Bmi1. Rb1 pathway status then dictates the opposing effects of mutant Ras on the ZEB1-miR-200 loop in primary versus cancer cells. This loop not only triggers EMT, surprisingly we show it acts downstream of Ras to regulate Bmi1 expression and thus the critical decision between oncogene-induced senescence and tumor initiation.
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sequential inductions of the ZEB1 Transcription Factor caused by mutation of rb and then ras proteins are required for tumor initiation and progression
Journal of Biological Chemistry, 2013Co-Authors: Yongqing Liu, Li Huang, Brian F. Clem, Sucheta Telang, Miriam Cuatrecasas, Ester Sancheztillo, A B Jenson, Jason Chesney, Antonio PostigoAbstract:Rb1 restricts cell cycle progression, and it imposes cell contact inhibition to suppress tumor outgrowth. It also triggers oncogene-induced senescence to block Ras mutation. Loss of the Rb1 pathway, which is a hallmark of cancer cells, then provides a permissive environment for Ras mutation, and Ras is sufficient for invasive tumor formation in Rb1 family mutant mouse embryo fibroblasts (MEFs). These results demonstrate that sequential mutation of the Rb1 and Ras pathways comprises a tumor initiation axis. Both Rb1 and Ras regulate expression of the Transcription Factor ZEB1, thereby linking tumor initiation to the subsequent invasion and metastasis, which is induced by ZEB1. ZEB1 acts in a negative feedback loop to block expression of miR-200, which is thought to facilitate tumor invasion and metastasis. However, ZEB1 also represses cyclin-dependent kinase (cdk) inhibitors to control the cell cycle; its mutation in MEFs leads to induction of these inhibitors and premature senescence. Here, we provide evidence for two sequential inductions of ZEB1 during Ras transformation of MEFs. Rb1 constitutively represses cdk inhibitors, and induction of ZEB1 when the Rb1 pathway is lost is required to maintain this repression, allowing for the classic immortalization and loss of cell contact inhibition seen when the Rb1 pathway is lost. In vivo, we show that this induction of ZEB1 is required for Ras-initiated tumor formation. ZEB1 is then further induced by Ras, beyond the level seen with Rb1 mutation, and this Ras superinduction is required to reach a threshold of ZEB1 sufficient for repression of miR-200 and tumor invasion.
Li Huang - One of the best experts on this subject based on the ideXlab platform.
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Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis
Nature communications, 2014Co-Authors: Yongqing Liu, Li Huang, Wei Wang, Guomin Jiang, Kevin C. Dean, Brian F. Clem, Sucheta Telang, Alfred B. Jenson, Miriam CuatrecasasAbstract:The Transcription Factor ZEB1 has been implicated in different steps of the metastatic cascade. Here the authors show that heterozygous loss of ZEB1 in a K-Ras-driven mouse model of lung cancer inhibits progression from lung adenomas to adenocarcinomas.
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the ZEB1 Transcription Factor acts in a negative feedback loop with mir200 downstream of ras and rb1 to regulate bmi1 expression
Journal of Biological Chemistry, 2014Co-Authors: Ester Sancheztillo, Li Huang, Sucheta Telang, Miriam Cuatrecasas, Xiaoqin Lu, Brian Clem, A B Jenson, Jason Chesney, Antonio PostigoAbstract:Ras mutations are frequent in cancer cells where they drive proliferation and resistance to apoptosis. However in primary cells, mutant Ras instead can cause oncogene-induced senescence, a tumor suppressor function linked to repression of the polycomb Factor Bmi1, which normally regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki). It is unclear how Ras causes repression of Bmi1 in primary cells to suppress tumor formation while inducing the gene in cancer cells to drive tumor progression. Ras also induces the EMT Transcription Factor ZEB1 to trigger tumor invasion and metastasis. Beyond its well-documented role in EMT, ZEB1 is important for maintaining repression of cdki. Indeed, heterozygous mutation of ZEB1 is sufficient for elevated cdki expression, leading to premature senescence of primary cells. A similar phenotype is evident with Bmi1 mutation. We show that activation of Rb1 in response to mutant Ras causes dominant repression of ZEB1 in primary cells, but loss of the Rb1 pathway is a hallmark of cancer cells and in the absence of such Rb1 repression Ras induces ZEB1 in cancer cells. ZEB1 represses miR-200 in the context of a mutual repression loop. Because miR-200 represses Bmi1, induction of ZEB1 leads to induction of Bmi1. Rb1 pathway status then dictates the opposing effects of mutant Ras on the ZEB1-miR-200 loop in primary versus cancer cells. This loop not only triggers EMT, surprisingly we show it acts downstream of Ras to regulate Bmi1 expression and thus the critical decision between oncogene-induced senescence and tumor initiation.
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Repression of ZEB1 and hypoxia cause sequential mesenchymal-to-epithelial transition and induction of aid, Oct4, and Dnmt1, leading to immortalization and multipotential reprogramming of fibroblasts in spheres.
Stem cells (Dayton Ohio), 2013Co-Authors: Yongqing Liu, Li Huang, Partha Mukhopadhyay, M. Michele Pisano, Douglas C. DeanAbstract:In this study, we demonstrate that sphere formation triggers immortalization and stable reprogramming of mouse fibroblasts. Cell contact signaling in spheres causes downregulation of the epithelial-to-mesenchymal transition Transcription Factor ZEB1 leading to rapid mesenchymal-to-epithelial transition. Hypoxia within spheres together with loss of ZEB1 repression synergize to cause superinduction of Hif1a, which in turn leads to induction of the DNA demethylase Aid/Aicda, demethylation of the Oct4 promoter/enhancer and multipotency. Oct4 and Nanog expression diminish when cells are removed from the hypoxic environment of spheres and placed in monolayer culture, but the cells retain multipotential capacity, demonstrating stable reprogramming and a gene expression pattern resembling adult stem cells. Oct4 has been shown to induce Dnmt1 in mesenchymal stem cells, and we link Oct4 and Dnmt1 to silencing of cell cycle inhibitory cyclin dependent kinase inhibitors and Arf, and immortalization of the reprogrammed fibroblasts. Sphere formation then represents a novel and rapid protocol for immortalization and stable reprogramming of fibroblasts to multipotency that does not require exogenous expression of a stem cell Factor or a lineage-specifying Transcription Factor. STEM Cells2013;31:1350–1362
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sequential inductions of the ZEB1 Transcription Factor caused by mutation of rb and then ras proteins are required for tumor initiation and progression
Journal of Biological Chemistry, 2013Co-Authors: Yongqing Liu, Li Huang, Brian F. Clem, Sucheta Telang, Miriam Cuatrecasas, Ester Sancheztillo, A B Jenson, Jason Chesney, Antonio PostigoAbstract:Rb1 restricts cell cycle progression, and it imposes cell contact inhibition to suppress tumor outgrowth. It also triggers oncogene-induced senescence to block Ras mutation. Loss of the Rb1 pathway, which is a hallmark of cancer cells, then provides a permissive environment for Ras mutation, and Ras is sufficient for invasive tumor formation in Rb1 family mutant mouse embryo fibroblasts (MEFs). These results demonstrate that sequential mutation of the Rb1 and Ras pathways comprises a tumor initiation axis. Both Rb1 and Ras regulate expression of the Transcription Factor ZEB1, thereby linking tumor initiation to the subsequent invasion and metastasis, which is induced by ZEB1. ZEB1 acts in a negative feedback loop to block expression of miR-200, which is thought to facilitate tumor invasion and metastasis. However, ZEB1 also represses cyclin-dependent kinase (cdk) inhibitors to control the cell cycle; its mutation in MEFs leads to induction of these inhibitors and premature senescence. Here, we provide evidence for two sequential inductions of ZEB1 during Ras transformation of MEFs. Rb1 constitutively represses cdk inhibitors, and induction of ZEB1 when the Rb1 pathway is lost is required to maintain this repression, allowing for the classic immortalization and loss of cell contact inhibition seen when the Rb1 pathway is lost. In vivo, we show that this induction of ZEB1 is required for Ras-initiated tumor formation. ZEB1 is then further induced by Ras, beyond the level seen with Rb1 mutation, and this Ras superinduction is required to reach a threshold of ZEB1 sufficient for repression of miR-200 and tumor invasion.