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  • 1
    Language: English
    In: Nucleic acids research, June 2014, Vol.42(10), pp.6436-47
    Description: The antimetabolite 5-fluorouracil is a widely used chemotherapeutic for the treatment of several solid cancers. However, resistance to 5-fluorouracil remains a major drawback in its clinical use. In this study we report that treatment of HeLa cells with 5-fluorouracil resulted in de novo assembly of stress granules. Moreover, we revealed that stress granule assembly under stress conditions as well as disassembly is altered in cells treated with 5-fluorouracil. Notably, we discovered that RACK1, a protein mediating cell survival and apoptosis, is a component of 5-fluorouracil-induced stress granules. To explore the mode of action of 5-fluorouracil accountable for de novo stress granule assembly, we analyzed 5-fluorouracil metabolites and noticed that stress granule assembly is caused by RNA, not DNA incorporating 5-fluorouracil metabolites. Interestingly, we observed that other RNA incorporating drugs also cause assembly of stress granules. Thus, our results suggest that incorporation of chemotherapeutics into RNA may result in stress granule assembly with potential significance in chemoresistance.
    Keywords: Stress, Physiological ; Antimetabolites, Antineoplastic -- Pharmacology ; Fluorouracil -- Pharmacology ; RNA -- Metabolism ; Ribonucleoproteins -- Metabolism
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 2
    Language: English
    In: Development, 07/15/2017, Vol.144(14), pp.e1.1-e1.1
    Keywords: Extracellular Signal-Regulated Kinase ; Pain Perception;
    ISSN: 0950-1991
    E-ISSN: 1477-9129
    Source: CrossRef
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  • 3
    Language: English
    In: 2012, Vol.7(11), p.e50134
    Description: Paralogs for several proteins implicated in neurodegenerative disorders have been identified and explored to further facilitate the identification of molecular mechanisms contributing to disease pathogenesis. For the disease-causing protein in spinocerebellar ataxia type 2, ataxin-2, a paralog of unknown function, termed ataxin-2-like, has been described. We discovered that ataxin-2-like associates with known interaction partners of ataxin-2, the RNA helicase DDX6 and the poly(A)-binding protein, and with ataxin-2 itself. Furthermore, we found that ataxin-2-like is a component of stress granules. Interestingly, sole ataxin-2-like overexpression led to the induction of stress granules, while a reduction of stress granules was detected in case of a low ataxin-2-like level. Finally, we observed that overexpression of ataxin-2-like as well as its reduction has an impact on the presence of microscopically visible processing bodies. Thus, our results imply a functional overlap between ataxin-2-like and ataxin-2, and further indicate a role for ataxin-2-like in the regulation of stress granules and processing bodies.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Molecular Biology ; Cell Biology ; Neurological Disorders ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(12), p.e115731
    Description: Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p〈0.05, fold-change〉1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination rather than enrichment of the subgroup of interest revealed proteins that define subclasses of TRPV1-positive neurons and suggests a novel paracrine circuit.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Nucleic acids research, 09 January 2017, Vol.45(1), pp.382-394
    Description: The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies.
    Keywords: RNA Splicing ; DNA-Binding Proteins -- Genetics ; Heat-Shock Response -- Genetics ; Nuclear Proteins -- Genetics ; RNA, Messenger -- Genetics ; RNA, Untranslated -- Genetics ; Transcription Factors -- Genetics
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 6
    Language: English
    In: The Journal of cell biology, 04 June 2018, Vol.217(6), pp.2167-2184
    Description: Type II isoforms of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA-II) contain a phosphorylatable epitope within the inhibitory domain of RII subunits (pRII) with still unclear function. In vitro, RII phosphorylation occurs in the absence of cAMP, whereas staining of cells with pRII-specific antibodies revealed a cAMP-dependent pattern. In sensory neurons, we found that increased pRII immunoreactivity reflects increased accessibility of the already phosphorylated RII epitope during cAMP-induced opening of the tetrameric RII:C holoenzyme. Accordingly, induction of pRII by cAMP was sensitive to novel inhibitors of dissociation, whereas blocking catalytic activity was ineffective. Also in vitro, cAMP increased the binding of pRII antibodies to RII:C holoenzymes. Identification of an antibody specific for the glycine-rich loop of catalytic subunits facing the pRII-epitope confirmed activity-dependent binding with similar kinetics, proving that the reassociation is rapid and precisely controlled. Mechanistic modeling further supported that RII phosphorylation precedes cAMP binding and controls the inactivation by modulating the reassociation involving the coordinated action of phosphodiesterases and phosphatases.
    Keywords: Research Articles ; 43 ; 23;
    ISSN: 00219525
    E-ISSN: 1540-8140
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  • 7
    Language: German
    In: BIOspektrum, 5/2017, Vol.23(3), pp.277-280
    Description: Pain sensitivity is strongly modulated by intracellular signalling. The analysis of pain signalling is hampered by small numbers of neurons, high cellular heterogeneity, and near absence of transfectability. HCS microscopy allowed us to proof that nociceptive neurons express specific signalling components, to analyze signalling activity of endogenous signalling components with single cell resolution, and thereby to suggest blockers of Nav1.7 as novel therapeutic approach to boost the efficacy of opioids.
    Keywords: Sodium Channels (Voltage-Gated) ; Pain Perception ; Intracellular Signalling ; Opioids;
    ISSN: 0947-0867
    E-ISSN: 1868-6249
    Source: Springer (via CrossRef)
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  • 8
    In: Pain, 2013, Vol.154(10), pp.2216-2226
    Description: SUMMARY: Quantification of signaling kinetics with automated microscopes identifies a novel sensitizing factor, bFGF, underlining the importance of the interaction of wound-healing factors and nociceptors. ABSTRACT: Growth factors such as nerve growth factor and glial cell line-derived neurotrophic factor are known to induce pain sensitization. However, a plethora of other growth factors is released during inflammation and tissue regeneration, and many of them are essential for wound healing. Which wound-healing factors also alter the sensitivity of nociceptive neurons is not well known. We studied the wound-healing factor, basic fibroblast growth factor (bFGF), for its role in pain sensitization. Reverse transcription polymerase chain reaction showed that the receptor of bFGF, FGFR1, is expressed in lumbar rat dorsal root ganglia (DRG). We demonstrated presence of FGFR1 protein in DRG neurons by a recently introduced quantitative automated immunofluorescent microscopic technique. FGFR1 was expressed in all lumbar DRG neurons as quantified by mixture modeling. Corroborating the mRNA and protein expression data, bFGF induced Erk1/2 phosphorylation in nociceptive neurons, which could be blocked by inhibition of FGF receptors. Furthermore, bFGF activated Erk1/2 in a dose- and time-dependent manner. Using single-cell electrophysiological recordings, we found that bFGF treatment of DRG neurons increased the current-density of NaV1.8 channels. Erk1/2 inhibitors abrogated this increase. Importantly, intradermal injection of bFGF in rats induced Erk1/2-dependent mechanical hyperalgesia. Perspective: Analyzing intracellular signaling dynamics in nociceptive neurons has proven to be a powerful approach to identify novel modulators of pain. In addition to describing a new sensitizing factor, our findings indicate the potential to investigate wound-healing factors for their role in nociception.
    Keywords: Pain ; Nociception ; Peripheral Sensory Neuron ; Sensitization Signaling ; Inflammatory Pain ; Wound Healing ; Quantitative Automated Microscopy ; Bfgf ; Fgf-2 ; Fgf-Β ; MAP Kinase ; Erk1/2 ; Na V 1.8 ; Voltage Gated Sodium Channels ; Randall Selitto;
    ISSN: 0304-3959
    E-ISSN: 18726623
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  • 9
    Language: English
    In: Journal of cell science, 01 July 2017, Vol.130(13), pp.2134-2146
    Description: Maturation of nociceptive neurons depends on changes in transcription factors, ion channels and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. Whether sensitization signaling also changes during development and aging remains so far unknown. Using a novel automated microscopy approach, we quantified changes in intracellular signaling protein expression and in their signaling dynamics, as well as changes in intracellular signaling cascade wiring, in sensory neurons from newborn to senescent (24 months of age) rats. We found that nociceptive subgroups defined by the signaling components protein kinase A (PKA)-RIIβ (also known as PRKAR2B) and CaMKIIα (also known as CAMK2A) developed at around postnatal day 10, the time of nociceptor maturation. The integrative nociceptor marker, PKA-RIIβ, allowed subgroup segregation earlier than could be achieved by assessing the classical markers TRPV1 and Na1.8 (also known as SCN10A). Signaling kinetics remained constant over lifetime despite in part strong changes in the expression levels. Strikingly, we found a mechanism important for neuronal memory - i.e. the crosstalk from cAMP and PKA to ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) - to emerge postnatally. Thus, maturation of nociceptors is closely accompanied by altered expression, activation and connectivity of signaling pathways known to be central for pain sensitization and neuronal memory formation.
    Keywords: Aging ; Development ; Extracellular Signal-Regulated Kinase ; Intracellular Signaling ; Nociception ; Protein Kinase A ; Aging -- Genetics ; Cyclic Amp -- Genetics ; Nociceptors -- Metabolism ; Sensory Receptor Cells -- Metabolism
    ISSN: 00219533
    E-ISSN: 1477-9137
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  • 10
    Language: English
    In: Molecular Medicine Reports, January-February 2011, Vol.4(1), pp.37-40
    Description: G-protein-coupled receptor 30 (GPR30) has been reported to act as a membrane-bound estrogen receptor that is involved in the mediation of non-genomic estradiol signalling. In this study, we demonstrated that male, but not female, GPR30-deficient mice suffer from impaired left‑ventricular cardiac function. Left ventricles from male mutant mice were enlarged. There were no malformations in the valves or outflow tract of the heart. Both the contractility and relaxation capacity of the left ventricle were reduced, leading to increased left‑ventricular end-diastolic pressure in GPR30-deficient mice. In conclusion, our data support a role for GPR30 in the gender-specific aspects of heart failure.
    Keywords: Biology;
    ISSN: 1791-2997
    E-ISSN: 17913004
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