Small and large intestine differ in basal ERK pathway activity
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ABSTRACT:
PROVIDER: PRJNA548339 | ENA |
REPOSITORIES: ENA
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Project description:In this experiment, we determined the differences in the transcriptomes of freshly isolated murine small intestine and colon derived crypts. The data shows that the mRNA profiles of the two tissues significantly differ in their ground state. Interestingly, we found that the expression levels of ERK pathway components as well as their positive and negative regulators significantly differ between small intestinal and colonic crypts. This observation indicates that the ERK pathway displays higher basal activity in the small intestine compared to the colon.
2021-06-30 | GSE132546 | GEO
Project description:Cardiomyocyte HIPK2 Maintains Basal Cardiac Function via ERK Signaling
| PRJNA562152 | ENA
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.
2015-04-24 | E-GEOD-68230 | 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.
2015-04-24 | GSE68230 | GEO
Project description:The EGFR/Ras/ERK signalling pathway is a primary driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. We explored these single-cell kinetic differences using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522 and found that ERK activity in invasive cells is similar in amplitude to non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. We traced this variability to a high degree of amphiregulin-mediated autocrine signalling by invasive cells. Dynamic ERK activity could be transferred from invasive to pre-malignant cells through paracrine signalling in co-culture, and could drive temporal variation in the expression of genes including Fra-1, c-Myc, and Egr1 at the single-cell level. Our findings establish a mechanism for the generation of tumour cell plasticity, in which paracrine signalling in the microenvironment is translated into continually shifting diversity in gene expression profiles, helping drive the phenotypic heterogeneity of tumour cells.
2020-08-01 | GSE118312 | GEO
Project description:Whole genome bisulfite-seq on 8 week adult mouse large intestine For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf
2021-11-04 | GSE188006 | GEO
Project description:Our genome-wide gene expression data indicate that, despite the lack of crypts, the rostral, mid, and caudal portions of the zebrafish intestine have distinct functions analogous to the mammalian small and large intestine, respectively. Organization of ridge structures represents a unique feature of zebrafish intestine, though they produce similar cross sections to mammalian intestines. Evolutionary lack of stomach, crypts, Paneth cells and submucosal glands has shaped the zebrafish intestine into a simpler but unique organ in vertebrate intestinal biology.
2010-06-29 | GSE20884 | GEO
Project description:The intestine is composed of an epithelial layer, containing rapidly proliferating cells that mature into two distinct anatomic regions, the small and the large intestine. Although previous studies have identified stem cells as the cell-of-origin for the whole intestine, no studies have compared stem cells derived from the small and large intestine. Here, we report intrinsic differences between these two populations of cells. Primary epithelial cells isolated from human fetal small and large intestine and expanded with Wnt agonist, R-spondin 2, displayed differential expression of stem cell markers and separate hierarchical clustering of gene expression involved in differentiation, proliferation and disease pathways. Using a three-dimensional in vitro differentiation assay, single cells derived from small and large intestine formed distinct organoid architecture with cellular hierarchy similar to that found in primary tissue. Our characterization of human fetal intestinal stem cells defies the classical definition proposed by most where small and large intestine are repopulated by an identical epithelial stem cell and raises the question of the importance of intrinsic and extrinsic cues in the development of intestinal diseases.
2015-01-15 | GSE56525 | GEO
Project description:The intestine is composed of an epithelial layer, containing rapidly proliferating cells that mature into two distinct anatomic regions, the small and the large intestine. Although previous studies have identified stem cells as the cell-of-origin for the whole intestine, no studies have compared stem cells derived from the small and large intestine. Here, we report intrinsic differences between these two populations of cells. Primary epithelial cells isolated from human fetal small and large intestine and expanded with Wnt agonist, R-spondin 2, displayed differential expression of stem cell markers and separate hierarchical clustering of gene expression involved in differentiation, proliferation and disease pathways. Using a three-dimensional in vitro differentiation assay, single cells derived from small and large intestine formed distinct organoid architecture with cellular hierarchy similar to that found in primary tissue. Our characterization of human fetal intestinal stem cells defies the classical definition proposed by most where small and large intestine are repopulated by an identical epithelial stem cell and raises the question of the importance of intrinsic and extrinsic cues in the development of intestinal diseases. 12 samples were analyzed. They consisted of human fetal small and large intestine (SI; n=6 and LI; n=6) stem cells, expanded with Wnt agonist and R-spondin 2. Differential expression of genes in epithelial cells from both the large and small intestine were observed.
2015-01-15 | E-GEOD-56525 | biostudies-arrayexpress
Project description:Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction—suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. In vivo rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Conclusions: Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling
2019-08-27 | GSE136308 | GEO