Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD008100
PROVIDER: PRJNA401815 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6008480.fastq.gz | Fastqsanger.gz | |||
| SRR6008471.fastq.gz | Fastqsanger.gz | |||
| SRR6008481.fastq.gz | Fastqsanger.gz | |||
| SRR6008472.fastq.gz | Fastqsanger.gz | |||
| SRR6008482.fastq.gz | Fastqsanger.gz |
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Project description:Mutations mimicking growth factor-induced proliferation and motility characterize aggressive subtypes of mammary tumors. To unravel novel players, we applied phosphoproteomics on untransformed mammary cells, which were pre-stimulated with the epidermal growth factor (EGF). This analysis identified ladinin-1 (LAD1), a hitherto poorly characterized protein, as a phosphor-effector of the EGF-to-ERK pathway. We report that LAD1 is essential for mammary cell proliferation and migration. LAD1 is transcriptionally induced, undergoes phosphorylation by EGF and partly co-localizes with actin stress fibers. Yeast 2-hybrids, proximity ligation and co-immunoprecipitation assays revealed that LAD1 binds with filamins, actin cross-linking proteins. Co-sedimentation analyses attribute to LAD1 a role in actin treadmilling, probably in collaboration with SFN/14-3-3sigma. Depletion of LAD1 led to a decrease in transcripts relevant to cell survival, and inhibited growth of mammary xenografts in an animal model. Furthermore, LAD1 is highly expressed in two aggressive subtypes of breast cancer, as well as predicts poor patient prognosis. This study identifies a new cytoskeletal component essential for cell migration and for the acquisition of oncogenic attributes by human mammary tumors.
2019-11-19 | PXD008100 | Pride
Project description:Mutations mimicking growth factor-induced proliferation and motility characterize some aggressive subtypes of mammary tumors. To unravel novel players, we applied phosphoproteomics on untransformed mammary cells, which were pre-stimulated with the epidermal growth factor (EGF). This analysis identified ladinin-1 (LAD1), a hitherto poorly characterized protein, as a phosphor-effector of the EGF-to-ERK pathway. We report that LAD1 is essential for mammary cell proliferation and migration. LAD1 is transcriptionally induced, undergoes phosphorylation by EGF and co-localizes with actin stress fibers. Yeast 2-hybrids and co-immunoprecipitation screens revealed that LAD1 binds with filamins, actin cross-linking proteins. Co-sedimentation analyses attribute to LAD1 a role in actin treadmilling, probably in conjuction with SFN/14-3-3sigma. Depletion of LAD1 led to a decrease in viability related transcripts, and inhibited growth of mammary xenografts in an animal model. Furthermore, LAD1 is highly expressed in two aggressive subtypes of breast cancer, as well as predicts poor patient prognosis. These studies identify a new cytoskeletal component essential for signal transduction and for the acquisition of oncogenic attributes by human mammary tumors.
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Project description:Patient-derived organoids and cellular spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a reconstituted basement membrane (rBM) in three dimensions (3D) supports the polarized, stress resilient tissue phenotype of mammary epithelial spheroids. Cells interacting with rBM in 3D had reduced levels of total and actin-associated filamin and decreased cortical actin tension that increased plasma membrane protrusions to promote negative plasma membrane curvature and plasma membrane protein associations linked to protein secretion. By contrast, cells engaging rBM in 2D had high cortical actin tension that forced filamin unfolding and endoplasmic reticulum (ER) associations. Enhanced filamin-ER interactions increased levels of PKR-like ER kinase effectors and ER-plasma membrane contact sites that compromised calcium homeostasis and diminished cell viability. Consequently, cells with low cortical actin tension had reduced ER stress and survived better. Consistently, cortical actin tension in cellular spheroids regulated polarized BM membrane deposition and sensitivity to exogenous stress. The findings implicate cortical actin tension-mediated filamin unfolding in ER function, and underscore the importance of tissue mechanics in organoid homeostasis.
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Project description:Actin assembly and dynamics control the shape, motility and functions of diverse cell types. Programme for controlling theses dynamics is hard-coded into actin binding proteins and regulatory proteins. Refilins (RefilinA and RefilinB) are short lived regulatory proteins that interact with the actin-binding protein Filamin to convert it from an actin branching protein into one that bundles. We here show that different mechanisms converge to increase Refilin level in brain NG2+ precursor cells (polydendrocytes) committed to differentiate into the oligodendrocyte lineage. RefilinA is up-regulated through transcriptional activation during commitment into oligodendrocyte progenitor cells (OPC). RefilinB expression relies on PDGF signalling and is further stabilized by a unique auto-inhibitory domain masking the adjacent conserved PEST degradation signal. In NG2+ precursor cells and OPC, the RefilinB/Filamin complex localizes on filipodia protrusions and filipodial processes. Stable ectopic expression of Refilins in cells stimulates membrane remodelling dynamics linked with filipodia growth. These studies extend the function of the Refilin/FLNA complex to cell membrane remodelling linked with reorganization of underlying actin cytoskeleton. We performed whole transcriptomic analysis on the three cell population derived from OPC cells. Three different cultures were done and for each experiment we compared each cell population (NG2+, NG2+/A2B5 and O4) to the other 2 cell populations.
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Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
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Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
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