Disease-specific alteration of karyopherin-alpha 4 subtype establishes feed-forward oncogenic signaling in squamous cell carcinoma
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ABSTRACT:
PROVIDER: PRJNA529089 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Nuclear import, mediated in part by karyopherin-alpha 4 (KPNA) subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of KPNA subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that KPNA4, encoding karyopherin-alpha 44 (KPNA4), is exclusively amplified and overexpressed in various forms of squamous cell carcinomas (SCCs). Depletion of KPNA4 suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, KPNA4 mediated nuclear transport of Ras-responsive element-binding protein (RREB1), which sustains Ras/ERK pathway signaling through repressing miR-143/145 expression. Notably, MAPK signaling enhanced trafficking activity of KPNA4 via phosphorylation of KPNA4 at Ser60. These data reveal that KPNA4 establishes a feed-forward cascade that potentiates Ras/ERK signaling in SCCs.
2019-12-22 | GSE128853 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE29182: Identification of active microRNA/transcription factor feed-forward loops during human adipogenesis (mRNA) GSE29185: Identification of active microRNA/transcription factor feed-forward loops during human adipogenesis (miRNA) Refer to individual Series
2011-12-20 | E-GEOD-29186 | biostudies-arrayexpress
Project description:Nuclear import, mediated in part by karyopherin-α (KPNA)/importin-α subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of KPNA subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that KPNA4, encoding karyopherin-α4 (KPNA4), is exclusively amplified and overexpressed in head and neck of squamous cell carcinoma (HNSCC). Depletion of KPNA4 attenuated nuclear localization signal-dependent transport activity and suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, KPNA4-mediated nuclear transport of Ras-responsive element-binding protein (RREB1), which sustains Ras/ERK pathway signaling through repressing miR-143/145 expression. Notably, MAPK signaling enhanced trafficking activity of KPNA4 via phosphorylation of KPNA4 at Ser60. These data reveal that KPNA4 establishes a feed-forward cascade that potentiates Ras/ERK signaling in HNSCC.
| S-EPMC7056645 | biostudies-literature
Project description:MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice
2016-09-01 | GSE86289 | GEO
Project description:MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice
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Project description:Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states.
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Project description:We compared transcriptomes of terminally differentiated mouse 3T3-L1 adipocytes [Series GSE14004] and human adipocytes to identify cell-specific differences. Gene expression and high content analysis (HCA) data identified the androgen receptor (AR) as both expressed and functional, exclusively during early human adipocyte differentiation. We used HCA to determine mechanisms of AR regulation and activity in human adipocytes. We found that AR is regulated in a feed-forward fashion by glucocorticoids.
2012-07-13 | GSE39342 | GEO
Project description:Post-transcriptional regulation of gene expression accomplished by microRNAs (miRNAs) importantly affects the complex gene regulatory network. In particular, miRNAs are known to be involved in recurrent motifs named miRNA-mediated feed forward loops (FFLs) where a transcription factor (TF) regulates a miRNA and they both regulate the expression level of a target RNA. Here, we focus on the identification of active FFLs during adipogenic differentiation. A list of putative feed-forward loops was generated based on sequence analysis of conserved and overrepresented motifs in the regulatory regions. Since this approach is not specific for adipogenesis and is known to generate false positive feed-forward loops, an experiment was designed to select active ones based on their dynamics using a model-based approach. Microarray time series of gene and miRNA expression data were collected at seven time points on human multipotent adipose-derived stem (hMADS) cells upon adipogenic differentiation. Three different dynamic models, sharing the same FFL topology but incorporating descriptions of increasing complexity of miRNA and mRNA dynamics, are identified on miRNA and mRNA expression data and compared based on identification criteria, namely: goodness of fit, precision of the estimates and comparison with submodels. 24 FFLs, able to properly reproduce data, are selected as active out of the 329 putative ones. This method considerably reduces the search space for new interactions between TFs, miRNAs and mRNAs and provides interesting biological results identifying genes known from the literature to be regulators in adipogenesis and adipocyte-related functions that can be interpreted as positive control of the validity of the apporoach. Therefore, the genes in the selected FFLs that are not yet known to be involved in this context are potential novel players in this regulatory network of adipogenesis and adipocyte function.
2011-12-20 | GSE29185 | GEO
Project description:Post-transcriptional regulation of gene expression accomplished by microRNAs (miRNAs) importantly affects the complex gene regulatory network. In particular, miRNAs are known to be involved in recurrent motifs named miRNA-mediated feed forward loops (FFLs) where a transcription factor (TF) regulates a miRNA and they both regulate the expression level of a target RNA. Here, we focus on the identification of active FFLs during adipogenic differentiation. A list of putative feed-forward loops was generated based on sequence analysis of conserved and overrepresented motifs in the regulatory regions. Since this approach is not specific for adipogenesis and is known to generate false positive feed-forward loops, an experiment was designed to select active ones based on their dynamics using a model-based approach. Microarray time series of gene and miRNA expression data were collected at seven time points on human multipotent adipose-derived stem (hMADS) cells upon adipogenic differentiation. Three different dynamic models, sharing the same FFL topology but incorporating descriptions of increasing complexity of miRNA and mRNA dynamics, are identified on miRNA and mRNA expression data and compared based on identification criteria, namely: goodness of fit, precision of the estimates and comparison with submodels. 24 FFLs, able to properly reproduce data, are selected as active out of the 329 putative ones. This method considerably reduces the search space for new interactions between TFs, miRNAs and mRNAs and provides interesting biological results identifying genes known from the literature to be regulators in adipogenesis and adipocyte-related functions that can be interpreted as positive control of the validity of the apporoach. Therefore, the genes in the selected FFLs that are not yet known to be involved in this context are potential novel players in this regulatory network of adipogenesis and adipocyte function.
2011-12-20 | GSE29182 | GEO
Project description:Post-transcriptional regulation of gene expression accomplished by microRNAs (miRNAs) importantly affects the complex gene regulatory network. In particular, miRNAs are known to be involved in recurrent motifs named miRNA-mediated feed forward loops (FFLs) where a transcription factor (TF) regulates a miRNA and they both regulate the expression level of a target RNA. Here, we focus on the identification of active FFLs during adipogenic differentiation. A list of putative feed-forward loops was generated based on sequence analysis of conserved and overrepresented motifs in the regulatory regions. Since this approach is not specific for adipogenesis and is known to generate false positive feed-forward loops, an experiment was designed to select active ones based on their dynamics using a model-based approach. Microarray time series of gene and miRNA expression data were collected at seven time points on human multipotent adipose-derived stem (hMADS) cells upon adipogenic differentiation. Three different dynamic models, sharing the same FFL topology but incorporating descriptions of increasing complexity of miRNA and mRNA dynamics, are identified on miRNA and mRNA expression data and compared based on identification criteria, namely: goodness of fit, precision of the estimates and comparison with submodels. 24 FFLs, able to properly reproduce data, are selected as active out of the 329 putative ones. This method considerably reduces the search space for new interactions between TFs, miRNAs and mRNAs and provides interesting biological results identifying genes known from the literature to be regulators in adipogenesis and adipocyte-related functions that can be interpreted as positive control of the validity of the apporoach. Therefore, the genes in the selected FFLs that are not yet known to be involved in this context are potential novel players in this regulatory network of adipogenesis and adipocyte function. Two independent cell culture experiments were performed as biological replicates during adipogenic differentiation of human mesenchymal stem cell. Cells where harvested at the pre-confluent stage as reference (day -3) and at seven subsequent time points during human adipogenic differentiation: day -2 and 0 before, and 1, 2, 5, 10, 15 days after induction of differentiation. All hybridizations were repeated with reversed dye assignment (dye-swap).
2011-12-20 | E-GEOD-29185 | biostudies-arrayexpress