Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Paola Ostano
PROVIDER: E-GEOD-65474 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J? in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Examination of genome-wide CSL binding sites in primary human dermal fibroblasts usinf two different antibodies against CSL
2015-08-24 | E-GEOD-59942 | biostudies-arrayexpress
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Human Dermal Fibroblasts were transfected with two different siRNA against CSL in parallel with a control siRNA. Total RNA was extracted 3 days post-transfection, followed by RNA-Seq analysis.
2015-08-24 | E-GEOD-65473 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-08-24 | GSE65474 | GEO
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control.
2015-08-24 | GSE59942 | GEO
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control.
2015-08-24 | GSE65473 | GEO
Project description:The expression of a large proportion of the fission yeast genome changes periodically with the cell cycle. Several key transcription factors have been identified that regulate these oscillating and interdependent waves of gene expression. However, for a significant number of cell cycle-regulated genes the regulator(s) driving these oscillations remain unknown. Cbf11 and Cbf12, the fission yeast CSL transcription factors, have been implicated in the regulation of cell cycle progression, yet the details of their functioning are poorly understood. Using a combination of transcriptome profiling and genome-wide mapping of CSL-DNA interactions we have identified a comprehensive set of CSL-regulated genes. Our data indicate that Cbf11 and Cbf12 contribute directly and indirectly to the regulation of periodically expressed genes in fission yeast. We show that during S phase/cytokinesis Cbf11 directly activates the transcription of several periodic genes required in the cell to prevent catastrophic mitosis. In agreement with these findings, multiple aspects of cell cycle progression are perturbed when CSL cellular levels are genetically manipulated. We have identified Cbf11 as a novel cell cycle phase-specific activator of genes required for proper coordination of cell and nuclear division, and prevention of catastrophic mitosis in fission yeast.
2015-09-18 | E-MTAB-2725 | biostudies-arrayexpress
Project description:Igh/Myc translocations underlie both sporadic Burkitt lymphoma (BL) and the endemic clinical form affecting African children infected with malaria. However, while sporadic translocations decapitate Myc from 5' proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc. The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. Here we recapitulate endemic BL-like translocations in plasmacytomas from uracil N-glycosylase (UNG) deficient mice. We demonstrate that in these animals, rare endemic-like translocations arise from non-targeted DNA breaks at Myc loci. Deep-sequencing analyses revealed that the deregulated 3' Igh enhancer alpha physically interacts with and remodels 0.45Mb of translocated chromatin. The results thus explain the long-range deregulation of oncogenes in human and mouse B cell tumors. ChIP-Seq, 4C, and 1 RNASeq samples used to characterize mouse plasmacytoma cell lines and in vitro activated mouse B cells. Biological replicates are present for many of the samples.
2013-07-04 | E-GEOD-48514 | biostudies-arrayexpress
Project description:Vertebrates have two cohesin complexes that consist of Smc1, Smc3, Rad21/Scc1 and either SA1 or SA2, but their functional specificity is unclear. Mouse embryos lacking SA1 show developmental delay and die before birth. Comparison of the genome wide distribution of cohesin in wild-type and SA1-null cells reveals that SA1 is largely responsible for cohesin accumulation at promoters and at sites bound by the insulator protein CTCF. As a consequence, ablation of SA1 alters transcription of genes involved in biological processes related to Cornelia de Lange syndrome (CdLS), a genetic disorder linked to dysfunction of cohesin. We show that the presence of cohesin-SA1 at the promoter of myc and of protocadherin genes positively regulates their expression, a task that cannot be assumed by cohesin-SA2. Cohesin binding pattern along some gene clusters is also affected by the lack of SA1, leading to dysregulation of the genes within. We hypothesize that impaired cohesin-SA1 function in gene expression underlies the molecular etiology of CdLS. Examination of genome wide distribution of cohesin subunits in wildtype and SA1-null cells
2012-03-15 | E-GEOD-32319 | biostudies-arrayexpress
Project description:We use a metabolic labeling strategy for directly measuring nucleosome turnover to determine the role of chromatin remodeler Chd1 on chromatin dynamics in mouse embryonic fibroblasts expressing with wildtype-Chd1 and dominant negative K510R-Chd1. We find that expression of K5 10R-Chd1 decreases nucleosome turnover at the promoter and increases turnover within the gene body. 10 Illumina sequencing samples and 4 Nimblegen array samples
2014-04-15 | E-GEOD-52501 | biostudies-arrayexpress
Project description:Chromatin immunoprecipitation (ChIP) and its derivatives are the main techniques used to determine transcription factor binding sites. However, conventional ChIP with sequencing (ChIP-seq) has problems with poor resolution and newer techniques require significant experimental alterations and complex bioinformatics. Here we build upon our high-resolution crosslinking ChIP-seq (X-ChIP-seq) method and compare it to existing methodologies. By using micrococcal nuclease, which has both endo- and exo-nuclease activity to fragment the chromatin and thereby generate precise protein-DNA footprints, high-resolution X-ChIP-seq achieves single base pair resolution of transcription factor binding. A significant advantage of this protocol is the minimal alteration to the conventional ChIP-seq workflow and simple bioinformatic processing. Using High-resolution X-ChIP-seq we determined the genome-wide binding profile of various DNA binding proteins.
2015-06-12 | E-GEOD-67454 | biostudies-arrayexpress