RAS-dependent ROS signaling in C. elegans.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA827175 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18771500_1.fastq.gz | Fastqsanger.gz | |||
| SRR18771500_2.fastq.gz | Fastqsanger.gz | |||
| SRR18771501_1.fastq.gz | Fastqsanger.gz | |||
| SRR18771501_2.fastq.gz | Fastqsanger.gz | |||
| SRR18771502_1.fastq.gz | Fastqsanger.gz |
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Project description:Mitochondrial superoxide produced by low concentrations of the pro-oxidant paraquat increases C. elegans lifespan. We found that paraquat acts by intensifying RAS-dependent ROS signaling (RDRS) to alter the expression of >50% of the genome and control animal composition and physiology. We show that RDRS is regulated by negative feedback from SOD-1-dependent conversion of superoxide into cytoplasmic hydrogen peroxide, which in turn acts on a redox-sensitive cysteine (C118) of the RAS homologue LET-60ras. Preventing C118 oxidation by replacement with serine, or mimicking oxidation by replacement with aspartic acid, leads to opposite changes in the expression of thousands of genes. We show that paraquat acts through RDRS to exacerbate and accelerate gene expression changes that are normally observed at the end of post-embryonic development. The identities of the genes affected by paraquat suggest that RDRS stimulation extends lifespan by increasing turnover and repair while moderating damage from metabolic activity.
2022-12-07 | GSE200912 | GEO
Project description:In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras.
2005-07-13 | E-SMDB-1398 | biostudies-arrayexpress
Project description:In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed
2005-07-22 | E-GEOD-2974 | biostudies-arrayexpress
Project description:In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2005-07-22 | GSE2974 | GEO
Project description:Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.
2022-10-14 | PXD031662 | Pride
Project description:The most common oncogenic mutations in multiple myeloma (MM) affect N- and K-RAS leading to constitutive activation of RAS-dependent signaling. Signal transduction via RAS, Raf and MAPK has been well described as a canonical pathway. In accordance with this assumption, we showed that the activity of the MEK/ERK module is strictly dependent on pan-Raf activity. However, inhibition of MEK/ERK has no or only minor effects on MM cell survival, whereas oncogenic Ras and pan-Raf critically contribute to survival of multiple myeloma cells. Therefore, we aimed to learn more about Raf-dependent but MEK-independent signaling effectors. We analyzed gene expression profiles in INA-6 cells after either pan-Raf inhibition with SB-590885 or MEK inhibition with PD-325901.
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Project description:Serum-dependent transcriptional networks identify distinct functional roles for H-ras and N-ras during initial stages of the cell cycle Using oligonucleotide microarrays, we compared gene expression transcriptional profiles corresponding to the initial cell cycle stages of mouse fibroblasts lacking H-Ras and/or NRas with those of matching, WT controls. The similarity of transcription profiles among serum-starved fibroblasts of all different WT and ras knockout genotypes tested, indicated that H-Ras and N-Ras do not play significant roles in control of transcriptional responses to serum deprivation stress. In contrast, genomic disruption of H-ras or N-ras, individually or in combination, determined highly specific, differential gene expression profiles in response to post-starvation stimulation with serum for 1 hour (G0/G1 transition) or for 8 hours (mid-G1 progression). The absence of N-Ras caused significantly higher changes than the absence of H-Ras on the wave of transcriptional activation linked to G0/G1 transition. In contrast, the absence of H-Ras affected more potently the profile of the transcriptional wave detected during mid-G1 progression. Functional analysis demonstrated a predominant functional association of H-Ras with growth and proliferation, whereas N-Ras exhibited a closer functional link to development or cell cycle regulation as well as immunomodulation and apoptosis. Mechanistic analysis indicated that ERK-dependent activation of Stat1 mediates the regulatory effect of N-Ras on defense and immunity, whereas the pro-apoptotic effects of N-Ras are mediated through ERK and p38 signaling. Our observations support previous reports of an absolute requirement for different peaks of Ras activity during the initial stages of the cell cycle and confirm the notion of functional specificity for the H-Ras and N-Ras isoforms. Keywords: different gene KO mice and time course
2009-09-01 | GSE14829 | GEO
Project description:The current study investigated the effect of RAS-induced ROS production on gene expression in normal human haematopoietic progenitor cells (HPC) using gene expression profiling (GEP) and assessed whether ROS-induced gene expression changes contributed to the pro-proliferative phenotype. In order to determine the ROS-specific GEP, Affymetrix Human Exon 1.0ST arrays were used for the comparison of mutant RAS and control cells cultured in the presence or absence of the NOX inhibitor, DPI, which strongly suppressed the production of ROS.
2015-11-30 | E-MTAB-3551 | biostudies-arrayexpress
Project description:CUX1 deficiency potentiates RAS signaling to drive malignancy
| PRJNA678951 | ENA
Project description:-7/del(7q) is genetic event prevalent in high-risk myeloid neoplasms. For reasons that are unclear, gain-of-function mutations in the RAS pathway frequently co-occur with monosomy 7. Here we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1. Concomitant mutations in RAS genes and CUX1 are wide-spread across tumor types, suggesting cooperativity in tumorigenesis. To test this, we generated mice with oncogenic NrasG12D and Cux1 knockdown. Double mutant mice developed myeloid malignancies with higher penetrance and faster onset than either single allele alone, with leukemic transformation in one third of cases. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem and progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through decreased transcriptional expression of negative regulators of RAS and PI3K signaling. Accordingly, NrasG12D;Cux1-knockdown HSPCs have heighted growth factor-sensitivity and downstream RAS pathway activation. Double mutant HSPCs were responsive to PIK3 or MEK inhibition, suggesting that these may be promising therapeutic targets in patients with 7/del(7q) malignancies. Our results implicate the loss of CUX1 as the underlying explanation for the association of -7/del(7q) with oncogenic RAS. Furthermore, we report the unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.
2021-11-16 | GSE161614 | GEO