Oncogenic K-Ras suppresses global miRNA function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA784250 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
2022-05-13 | GSE189705 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189701 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189700 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189704 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189702 | GEO
Project description:Ephexin1 was initially identified as a neuronal guanine nucleotide exchange factor involved in the control of neuronal development and synaptic homeostasis. Here, we demonstrate that the induction of Ephexin1 expression by an oncogenic K-Ras mutation amplifies the MAPK signaling via direct interaction with oncogenic Ras and contributes to colon and lung tumorigenesis. Ephexin1 cooperates with mutant Ras to accelerate skin tumorigenesis in vivo. In addition, we have demonstrated that the functionally relevant interaction between oncogenic K-Ras and Ephexin1. Together, these findings suggest that Ephexin1 serves as a positive regulator of Ras-driven oncogenesis and potentially represents a novel target for therapeutic intervention.
2021-10-27 | GSE147809 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189699 | GEO
Project description:Approximately 50% of prostate cancers have chromosomal translocations resulting in the over-expression one of four ETS family transcription factors. However, it is not known why these four four family members are selected for oncogenic roles, while other ETS proteins are not. We found that the four oncogenic ETS family members have a specific role in prostate cell migration. Using chromatin immunoprecipitation coupled with next-generation sequencing, this specific biological function was matched to a specific set of genomic targets highlighted by the presence of an AP-1 binding site. ETS/AP-1 binding sites are prototypical Ras-responsive elements, but oncogenic ETS proteins could activate a Ras/MAPK transcriptional program in the absence of MAPK activation. These findings indicate that the specific function of ETS proteins over-expressed in prostate cancer is the activation of a Ras/MAPK gene expression program in the absence of signaling pathway mutations. ChIP sequencing two transcription factors in PC3 cells, four transcription factors plus a FLAG control in RWPE-1 cells and input DNA sequencing from each cell line.
2011-10-19 | E-GEOD-29808 | biostudies-arrayexpress
Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1?/? MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis. RNA was isolated from RasV12 transformed NIH/3T3 cells (RasV12 cells) treated with 20?M U0126 or 500U/ml IFN-?, or left untreated, for 6 hours, triplicate biological samples (9 samples).
2014-11-13 | E-GEOD-49469 | biostudies-arrayexpress
Project description:Ephexin1 cooperates with K-Ras to promote oncogenic Ras-driven tumorigenesis
| PRJNA619876 | ENA