Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis
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PROVIDER: PRJNA665043 | ENA |
REPOSITORIES: ENA
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Project description:Mice with hepatocyte-specific deletion of both Shp2 and IkkB were generated, which disrupted basal levels of Ras-ERK and NF-kB signaling. These mice exhibited accelerated liver tumor formation compared to either single knockout alone. RNA-Seq analysis of whole liver and isolated hepatocytes from all genotypes were performed to identify tumor-promoting factors in the DKO model. Along with inflammatory and
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Project description:Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling.
2015-08-22 | GSE63497 | GEO
Project description:Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling.
2015-08-22 | GSE64190 | GEO
Project description:Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling. We performed ChIP-seq to assess the global changes in the histone modifications H3K27ac (AC), H3K4me1 (me1), and H3K4me3 (me3) upon loss of feedback regulation through Sprouty (Spry) deletion, and upon unrestrained signaling driven by oncogenic HRasG12V. ChIP-seq was performed in biological duplicate; replicate2 is indicated in the sample name. Spry124fl/fl (VEC) and Spry124-/- (CRE) MEFs were profiled in three conditions: unsynchronized (U), serum starved (S), and serum starved and FGF treated (F). Spry124fl/fl (VEC) MEFs transduced with empty vector (EV) control or HRasG12V (HRas) were profiled in the unsynchronized state.
2015-08-22 | E-GEOD-64190 | biostudies-arrayexpress
Project description:Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling. We assessed gene expression changes upon loss of feedback regulation through Sprouty (Spry) deletion, and upon unrestrained signaling driven by mutant oncogenes. RNA-seq was performed in biological triplicate; replicate number is included in the sample name. Spry124fl/fl (VEC) and Spry124-/- (CRE) MEFs were profiled in three conditions: unsynchronized (U), serum starved (S), and serum starved and FGF treated (F). Spry124fl/fl (VEC) MEFs transduced with empty vector (EV) control or the indicated oncogenes (KRasG12V, HRasG12V, and BRafV600E) as well as Spry124-/- (CRE) MEFs transduced with EV control were profiled in the unsynchronized state.
2015-08-22 | E-GEOD-63497 | biostudies-arrayexpress
Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.
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Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results.
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Project description:Studies were undertaken to determine whether oscillatory behavior in the extracellular signal regulated kinase (ERK) pathway results in unique gene regulation patterns. Microarray analysis was performed on three subcloned populations of human keratinocytes with distinct ERK signaling/oscillation phenotypes. Microarray analysis identified 45 genes that overlapped between 2 subclones with oscillation phenotypes but not in the subclone which is non-oscillatory. Transcription factor networks revealed a role for MED1 in mediating ERK oscillation-dependent gene expression, which was confirmed with Western blot analysis. Further experimentation confirmed a role for p38 in the mediation of MED1 phosphorylation and ERK oscillatory behavior. hTERT-immortalized normal human keratinocytes (provided by Dr. Jerry Shay, The University of Texas Southwestern Medical Center) were stably transfected with ERK1-green fluorescent protein chimera and stable subclones were isolated with distinct ERK activation/oscillation patterns: Clone #1 exhibits transient ERK activation with ligand activation but does not oscillate; Clone #2 exhibits persistent ERK oscillations that are dependent on ligand activation; and Clone #3 exhibits spontaneous ERK oscillations in the absence of ligand activation.
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Project description:Studies were undertaken to determine whether oscillatory behavior in the extracellular signal regulated kinase (ERK) pathway results in unique gene regulation patterns. Microarray analysis was performed on three subcloned populations of human keratinocytes with distinct ERK signaling/oscillation phenotypes. Microarray analysis identified 45 genes that overlapped between 2 subclones with oscillation phenotypes but not in the subclone which is non-oscillatory. Transcription factor networks revealed a role for MED1 in mediating ERK oscillation-dependent gene expression, which was confirmed with Western blot analysis. Further experimentation confirmed a role for p38 in the mediation of MED1 phosphorylation and ERK oscillatory behavior.
2014-03-13 | GSE55823 | GEO