P53- repressed miRNAs are involved with E2F in a feed forward loop promoting proliferation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE12821 | GEO | 2008/09/25
SECONDARY ACCESSION(S): PRJNA111127
REPOSITORIES: GEO
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Project description:There is a distinctive miRNA expression profile between early (young) and replicative senescence (old). We observed a cluster of miRNAs that were repressed upon senescence in both MRC-5 and WI-38 fibroblast cells. miRNAs profiling in young and senescence human emryonic fibroblasts (MRC-5 and WI-38)
2010-05-19 | E-GEOD-12821 | biostudies-arrayexpress
Project description:miRNA expression profiles of WI38 primary human fibroblasts with an active or inactive p53. Cells were compared under normal untreated conditions (young and proliferating cells), after DNA damage with Doxorubicin, and upon entry into replicative senescence. Keywords: miRNA, WI-38, p53, GSE56, Senescence, Doxorubicin, Cancer, DNA-damage, fibroblasts.
2008-09-21 | GSE12450 | GEO
Project description:miRNA expression profiles of WI38 primary human fibroblasts with an active or inactive p53. Cells were compared under normal untreated conditions (young and proliferating cells), after DNA damage with Doxorubicin, and upon entry into replicative senescence. Keywords: miRNA, WI-38, p53, GSE56, Senescence, Doxorubicin, Cancer, DNA-damage, fibroblasts. 6 samples of WI38 cells were analyzed on 12 Exiqon miRcurry LNA arrays in biological duplicates (2 different cell culture plates for each experimental condition). The six conditions included: 1. [Con_Young] - Primary Young WI38 cells (passage 20) with a control retroviral vector (pLXSN-NEO). Untreated. 2. [GSE_Young] -Primary Young WI38 cells (passage 20) with a retroviral vector encoding for the p53-inactivating peptide GSE56 (pLXSN-NEO-GSE56).Untreated. 3. [Con_Dox] -Primary Young WI38 cells (passage 20) with a control retroviral vector (pLXSN-NEO). Treated with Doxorubicin (0.2 micrograms/ml) for 24 hours). 4. [GSE_Dox] Primary Young WI38 cells (passage 20) with a retroviral vector encoding for the p53-inactivating peptide GSE56 (pLXSN-NEO-GSE56). Treated with Doxorubicin (0.2 micrograms/ml) for 24 hours). 5. [Con_Old] - Sesescent WI38 cells (passage 30) with a control retroviral vector (pLXSN-NEO). Untreated. 6. [GSE_Old] - Senescent WI38 cells (passage 26) with a retroviral vector encoding for the p53-inactivating peptide GSE56 (pLXSN-NEO-GSE56).Untreated. RNA was extracted with TRI-Reagent and sent for labeling and hybridization in Exiqon laboratories (In Denamark). Samples were labeled with Cy5. Reference sample (Cy3) was an RNA mix of all samples. Log2 for Ratio(Cy5/Cy3) was used for further analysis.
2010-05-19 | E-GEOD-12450 | biostudies-arrayexpress
Project description:Analysis of miRNA expression in human breast cancer samples with Agilent's miRNA arrays. These samples are part of a study where we have investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. We observed that indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Abstract of paper: Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. Indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these microRNAs silence anti-proliferative genes, which themselves are E2F1 targets. Thus, microRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative microRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Together these findings position microRNAs as novel key players in the mammalian cellular proliferation network. Keywords: Breast Cancer, miRNA, p53. 18 Primary human breast cancer samples analyzed for their miRNA expression. From two to four replicates were performed for each sample. Quality check (QC) were performed with Feature Extraction 9.1.3.44 and arrays not passing QC were excluded
2008-09-22 | E-GEOD-12848 | biostudies-arrayexpress
Project description:Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs (miRNAs) in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs. Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53. These miRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these miRNAs silence antiproliferative genes, which themselves are E2F1 targets. Thus, miRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Taken together, these findings position miRNAs as novel key players in the mammalian cellular proliferation network.
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Project description:Analysis of miRNA expression in human breast cancer samples with Agilent's miRNA arrays. These samples are part of a study where we have investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. We observed that indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Abstract of paper: Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. Indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these microRNAs silence anti-proliferative genes, which themselves are E2F1 targets. Thus, microRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative microRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Together these findings position microRNAs as novel key players in the mammalian cellular proliferation network. Keywords: Breast Cancer, miRNA, p53. 18 Primary human breast cancer samples analyzed for their miRNA expression. From two to four replicates were performed for each sample. Quality check (QC) were performed with Feature Extraction 9.1.3.44 and arrays not passing QC were excluded
| S-ECPF-GEOD-12848 | biostudies-other
Project description:Analysis of miRNA expression in human breast cancer samples with Agilent's miRNA arrays. These samples are part of a study where we have investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. We observed that indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Abstract of paper: Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcription regulators, E2F and p53, their targets, and a family of 14 microRNAs. Indicative of their significance, expression of these microRNAs is down-regulated in senescent cells and in breast cancers harboring wild-type p53. These microRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these microRNAs silence anti-proliferative genes, which themselves are E2F1 targets. Thus, microRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative microRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Together these findings position microRNAs as novel key players in the mammalian cellular proliferation network. Keywords: Breast Cancer, miRNA, p53.
2008-09-23 | GSE12848 | GEO
Project description:Hypothalamic feeding circuits have been identified as having innate synaptic plasticity, mediating adaption to the changing metabolic milieu by controlling responses to feeding and obesity. However, less is known about the regulatory principles underlying the dynamic changes in agouti-related protein (AgRP) perikarya, a region crucial for gating of neural excitation and, hence, feeding. Here we show that AgRP neurons activated by food deprivation, ghrelin administration, or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter GABA released by AgRP neurons that evoked this astrocytic response; this in turn resulted in increased glial ensheetment of AgRP perikarya by glial processes and increased excitability of AgRP neurons. We also identified astrocyte-derived prostaglandin E2, which directly activated - via EP2 receptors - AgRP neurons. Taken together, these observations unmasked a feed-forward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding, and overfeeding.
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Project description:Finite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflick in vitro using WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.
2024-09-24 | GSE276046 | GEO
Project description:Finite replicative potential is a defining feature of non-transformed somatic cells, first established by Leonard Hayflick in vitro using WI-38 human lung fibroblasts. Once proliferative capacity is exhausted due to telomere shortening, cells enter into a state called replicative senescence, which can be avoided through ectopic expression of telomerase reverse transcriptase (hTERT). As WI-38 cells approach replicative arrest, molecular pathways linked to mechanotransduction are induced, including YAP signaling, but the potential interplay between replicative lifespan and the mechanical environment of the cell remains unexplored. Here, we investigate the influence of mechanosensation on the trajectory towards replicative arrest taken by WI-38 cells by growing cells on substrates of varying stiffnesses. Matrix softening slowed proliferation, altered cellular phenotypes, and shortened proliferative lifespan while hTERT expression abrogated or reduced these responses. Our analyses of bulk and single-cell RNA-sequencing and ATAC-sequencing revealed the emergence of a unique G1 transcriptional state on soft substrates, characterized by an AP-1 transcription factor program, which failed to manifest with hTERT expression. Together, these findings reveal how the mechanical environment alters WI-38 cell proliferative lifespan and dictates unique paths towards growth arrest.
2024-09-24 | GSE276045 | GEO