Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1261227 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33511972_1.fastq.gz | Fastqsanger.gz | |||
| SRR33511972_2.fastq.gz | Fastqsanger.gz | |||
| SRR33511973_1.fastq.gz | Fastqsanger.gz | |||
| SRR33511973_2.fastq.gz | Fastqsanger.gz | |||
| SRR33511974_1.fastq.gz | Fastqsanger.gz |
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Project description:The Hedgehog (Hh) pathway is essential for tissue homeostasis, and misregulation of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase 2 (GRK2)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking vertebrate Hh signal transduction at the membrane to transcription factor activation in the nucleus. In contrast to existing models, our work shows that this aspect of Hh signaling is fundamentally similar between species. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades.
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Project description:The nervous system plays an increasingly appreciated role in the regulation of cancer. In gliomas, neuronal activity drives tumor progression through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumor proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signaling through the receptor TrkB (tropomyosin receptor kinase B), BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity that contributes to memory and learning in the healthy brain. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells robustly inhibits tumor progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.
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Project description:The nervous system plays an increasingly appreciated role in the regulation of cancer. In gliomas, neuronal activity drives tumor progression through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumor proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signaling through the receptor TrkB (tropomyosin receptor kinase B), BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity that contributes to memory and learning in the healthy brain. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells robustly inhibits tumor progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.
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Project description:The Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.
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Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Nestin+ and Nestin- GNPs (granule neuron precursors) were purified from Nestin-CFP/Math1-Cre/Ptch1-loxp cerebella at postnatal day 4 by FACs, and total RNA from these two cell populations were extracted, and then labeled and hybridized to Affymetrix Mouse Genome 430 2.0 arrays.
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Project description:Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate the activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data, and an ETS1 deletion line are used to show that the opposite function of ETS2 is due to binding site competition and a weaker activation function of ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor BS69 (ZMYND11). Gene expression data from tumor cohorts was then used to show that BS69 expression level in tumors correlates with oncogenic and tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner.
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