Ontology highlight
ABSTRACT:
PROVIDER: PRJNA337948 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4004611.fastq.gz | Fastqsanger.gz | |||
| SRR4004611_1.fastq.gz | Fastqsanger.gz | |||
| SRR4004611_2.fastq.gz | Fastqsanger.gz | |||
| SRR4004612.fastq.gz | Fastqsanger.gz | |||
| SRR4004612_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours
2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress
Project description:A variety of cancers utilize RAS-regulated signaling pathways to promote oncogenic phenotypes. A widely studied example is pancreatic cancer, where mutant KRAS signaling leads to activation of MEK/ERK kinases and downstream signaling which promotes oncogenic mechanisms, including cell proliferation. Importantly, ERK inhibitors have shown efficacy in some cancer clinical trials. Previously, others have studied the effects of the related kinases TBK1 and IKKε in pancreatic cancer where they have been shown to promote cell survival. Here, we show that RAS/MAPK signaling promotes expression of IKKε through control of protein stability and not through control of RNA levels. RNAseq analysis indicate that TBK1 and IKKε contribute to the expression of a subset of ERK-regulated genes. Potentially related to the effects on IKKε, proteomic analysis reveals that ERK functions to stabilize a relatively large set of proteins independent of RNA regulation. Knockdown of IKKε and TBK1 individually does not affect growth of MIA PaCa-2 pancreatic cancer cells, but dual knockdown significantly inhibits MIA PaCa-2 growth which is mediated through cell death. Concurrent silencing or inhibition of both TBK1 and IKKε also reduces tumor sphere growth in MIA PaCa-2 cells, correlating with a loss of stemness pathways found with RNAseq. The data suggest the importance of regulation of IKKε by ERK in pancreatic cancer cells and of the combined oncogenic activity of TBK1 and IKKε.
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Project description:Long noncoding RNAs play important roles in the spatial and temporal regulation of muscle development and regeneration. Nevertheless, the determination of their biological functions and mechanisms underlying muscle satellite cell differentiation remains challenging. Here, we identified a novel lncRNA named lncMREF as a specific positive regulator of muscle regeneration in mice, pigs and humans. Functional studies demonstrated that lncMREF is significantly upregulated in activated skeletal muscle satellite cells and promotes myogenic differentiation and muscle regeneration. Mechanistically, lncMREF interacts with Smarca5 to promote chromatin remodeling and accessibility when muscle satellite cells are activated, thereby facilitating genomic binding of p300/H3K27 to upregulate the expression of myogenic regulators, such as MyoD and cell differentiation. Our results unravel a new temporal-specific epigenetic regulation during muscle regeneration and reveal that lncMREF/Smarca5-mediated epigenetic programming is responsible for muscle satellite cell differentiation, which provides new insights into the regulatory mechanism of muscle regeneration in adult animals.
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Project description:Long noncoding RNAs play important roles in the spatial and temporal regulation of muscle development and regeneration. Nevertheless, the determination of their biological functions and mechanisms underlying muscle satellite cell differentiation remains challenging. Here, we identified a novel lncRNA named lncMREF as a specific positive regulator of muscle regeneration in mice, pigs and humans. Functional studies demonstrated that lncMREF is significantly upregulated in activated skeletal muscle satellite cells and promotes myogenic differentiation and muscle regeneration. Mechanistically, lncMREF interacts with Smarca5 to promote chromatin remodeling and accessibility when muscle satellite cells are activated, thereby facilitating genomic binding of p300/H3K27 to upregulate the expression of myogenic regulators, such as MyoD and cell differentiation. Our results unravel a new temporal-specific epigenetic regulation during muscle regeneration and reveal that lncMREF/Smarca5-mediated epigenetic programming is responsible for muscle satellite cell differentiation, which provides new insights into the regulatory mechanism of muscle regeneration in adult animals.
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