Ontology highlight
ABSTRACT:
PROVIDER: PRJNA757251 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15593535_1.fastq.gz | Fastqsanger.gz | |||
| SRR15593535_2.fastq.gz | Fastqsanger.gz | |||
| SRR15593536_1.fastq.gz | Fastqsanger.gz | |||
| SRR15593536_2.fastq.gz | Fastqsanger.gz | |||
| SRR15593537_1.fastq.gz | Fastqsanger.gz |
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Project description:We transfected HEK-293T cells to express RfA1. The RNA-Seq results indicates that Genes evolved in biological processes such as “regulation of microtubule cytoskeleton organization”, “microtubule polymerization or depolymerization”, “microtubule nucleation” were found to respond to RfA1 expression. Correspondingly, these microtubule relevant genes were also sorted to cellular component items, including “spindle microtubule”, “spindle pole centrosome”, “mitotic spindle”, “spindle” , which indicates the tight relationship between RfA1 and microtubules.
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Project description:Studying the evolution of binding preferences for 30 paralog TF pairs in S.cerevisiae
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Project description:The lack of a cure for metastatic prostate cancer (PCa) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the molecular mechanism of action of the natural product 6-acetoxy-anopterine (6-AA) in malignant cells of the prostate. This potent cytotoxic alkaloid from the endemic Australian tree Anopterus macleayanus induced at low nanomolar doses a strong accumulation of LNCaP and PC3 PCa cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared to vinblastine, highlighting pathways involved in mitosis, microtubule spindle organisation and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced microtubule polymer mass in vitro. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids or 2-methoxyestradiol did not confer cross-resistance to 6-AA, suggesting a different mechanism of microtubule interaction. Finally, 6-AA is the first-in-class microtubule inhibitor that features the unique anopterine scaffold. Altogether, this study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease.
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Project description:BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs, and new vulnerabilities in cells after emergence of resistance.
2020-04-08 | GSE131980 | GEO
Project description:BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs, and new vulnerabilities in cells after emergence of resistance.
2020-04-08 | GSE131977 | GEO
Project description:This model is built by COPASI 4.24(Build 197), based on paper:
Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment.
Author:
James M. Greene, Jana L. Gevertz, Eduardo D. sontag
Abstract:
PURPOSE:Drug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise from random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself via either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols. MATERIALS AND METHODS:To better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance. RESULTS:Our model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable and propose an in vitro protocol that could be used to determine a treatment's propensity to induce resistance.
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Project description:Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces the assembly of actin comet tails on mitochondria that propel these organelles to drive spatial mixing,resulting in their equitable inheritance by daughter cells. In contrast, during interphasethe cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. Depletion of FMNL1 ablates the actin wave, allowing us to assess the functional consequences in interphase cells. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigated the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, fission results. In striking contrast, upon microtubule depolymerization actin wave-enveloped mitochondria in interphase cells display comet tail motility characteristic of metaphase cells, which are devoid of microtubule-mitochondria interactions, suggesting that microtubule tethering inhibits comet tail-driven motility.
2024-06-23 | PXD050085 | Pride
Project description:Swift and complete spindle disassembly in late mitosis is essential for cell survival, yet how it happens is largely unknown in mammalian cells. Here we used real-time live cell microscopy and biochemical assays to show that the primordial dwarfism (PD)-related cysteine-rich protein CRIPT dictates the spindle disassembly in a redox-dependent manner in human cells. This previously reported cytoplasmic protein was found to have a confined nuclear localization with a nucleolar concentration during interphase but was distributed to spindles and underwent redox modifications to form disulfide bonds in CXXC pairs during mitosis. Then, it directly interacted with, and might transfer a redox response to, tubulin subunits via a putative redox exchange among cysteine residues to induce microtubule depolymerization. Expression of CRIPT proteins with mutations of these cysteine residues blocked spindle disassembly, generating two cell types with long-lasting metaphase spindles or spindle remnants. Live-cell recordings of a disease-relevant mutant (CRIPTC3Y) revealed that microtubule depolymerization at spindle ends during anaphase and the entire spindle dissolution during telophase might share a common CRIPT-bearing redox-controlled mechanism.
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