Redox control of the cAMP/PKA pathway during protein misfolding stress
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ABSTRACT:
PROVIDER: PRJEB39415 | ENA |
REPOSITORIES: ENA
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Project description:Signal transduction plays a crucial role in defending against external environmental challenges, which can modulate the cellular response to external stimuli. cAMP/PKA signaling pathway is one of the most important signaling circuits and is evolutionarily conserved in eukaryotes. A. oligospora is a typical nematode-trapping fungi that can specialize adhesive network traps to kill nematodes after sensing the signals. To elucidate the biological roles of cAMP-PKA signaling pathway, we characterized an adenylate cyclase orthologous protein, AoAcy, a cAMP-dependent protein kinase regulator, AoPKaR, and two cAMP-dependent protein kinase catalytic subunits, AoPKaCs in A. oligospora. Furthermore, phenotypic analysis of the gene disruption strains showed that the deletion of AoAcy resulted in a significant decrease in the content of cAMP and arthrobotrisins, and the results indicated that AoAcy, AoPKaR and AoPKaC1 were involved in the hyphae growth, trap morphogenesis, sporulation, stress resistance and autophagy. In addition, AoAcy and AoPKaC1 were also participated in the regulation of mitochondria, thereby affecting energy metabolism. While AoPKaC2 only affected sporulation, the number of nuclei and autophagy. Collectively, these findings highlight the essential role of cAMP/PKA signaling pathway in A. oligospora and provide insights into the regulation mechanisms of signaling pathways in trap formation and sporulation.
2022-08-13 | GSE210886 | GEO
Project description:Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation. Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation.
2021-08-24 | GSE182498 | GEO
Project description:Protein aggregation is the abnormal association of misfolded proteins into larger, often insoluble structures that can be toxic during ageing and in protein aggregation-associated diseases. This RNA-seq study in Saccharomyces cerevisiae investigated the role of Tsa1, which is a member of the highly conserved 2-Cys peroxiredoxin (Prx) enzyme family, on protein aggregation.
2021-04-19 | E-MTAB-9355 | biostudies-arrayexpress
Project description:The conserved cAMP-dependent protein kinase (PKA) holoenzyme is composed of two catalytic and two regulatory subunits. It plays critical roles in the regulation of many biological processes in eukaryotic organisms. In the human fungal pathogen Candida albicans, the PKA kinase has been extensively investigated for its importance in the regulation of morphological transitions and virulence. It has been long thought that the PKA catalytic subunit is essential for cell viability in C. albicans. Paradoxically, the single adenylyl cyclase-encoding gene, CRY1, which is required for the production of cAMP in C. albicans, is not essential for cell growth. In this study, we successfully generated a null double mutant of TPK1 and TPK2 (tpk2/tpk2 tpk1/tpk1 or t2t1), which encode two isoforms of the PKA catalytic subunit in C. albicans. We reevaluated the roles of the PKA catalytic subunit in cell growth and phenotypic transitions. Inactivation of the PKA catalytic subunit by deletion of both TPK1 and TPK2 blocked filamentation and dramatically attenuated the ability of white-to-opaque switching, but promoted sexual mating in C. albicans. Tpk2 plays a major role in these regulations, while Tpk1 generally functions as a negative regulator in morphological transitions and sexual mating. A comparative transcriptomic analysis demonstrated that the t2t1 and cyr1/cyr1 mutants exhibited similar global gene expression profiles. Compared to the WT strain, the general transcriptional activity and expression of genes involved in metabolism, translation, biosynthesis, adhesion and filamentation are significantly decreased in both the t2t1 and cyr1/cyr1 mutants. And a portion of stress-response and cell wall-related genes were upregulated in these mutants, which is consistent with their increased ability of anti-stresses. To further explore the global regulatory role of the PKA kinase, we performed quantitative phosphoproteomics analysis. Combining with bioinformatics analyses, we identified 181 potential PKA phosphorylation targets, which represent 148 unique proteins involved in a wide spectrum of biological processes. Cell wall and membrane-related proteins (e.g. Ecm3, Bni1, and Smi1) were enriched in Tpk1-specific targets, while Tpk2-specific substrates include transporters, filamentation and cytoskeleton-related proteins (e.g. Smf3, Sep7, and Mhp1). There were also many Tpk1 and Tpk2 overlapped and coordinately regulated-substrates. Our study clarifies the essentiality of the PKA catalytic subunit and shed new insights into the global regulatory features of the cAMP/PKA pathway in C. ablicans. The t2t1 null mutant generated in this study would also be a new resource for the field to study this important pathway.
2017-08-18 | GSE92621 | GEO
Project description:Vasopressin/cAMP/protein kinase A (PKA)/aquaporin-2 (AQP2) water channels signaling in the kidneys is a canonical pathway that determines AQP2 activity in response to body fluid balance. AQP2 phosphorylation by PKA increases water reabsorption from urine for the prevention of further water loss. We used several activators of cAMP/PKA signaling as screening tools to generate various phosphorylation patterns of PKA substrates and AQP2 in a mouse cortical collecting duct principal cell line (mpkCCDcl4). We next quantified phosphorylation levels of PKA substrates and AQP2 after western blot analysis using a phospho-PKA substrates antibody. Finally, we screen for PKA substrates whose phosphorylation levels were well correlated with those of AQP2. Immunoprecipitation with a phospho-PKA substrates antibody followed by mass spectrometry analysis revealed that the leading candidate in this assay proved to be a lipopolysaccharide-responsive and beige-like anchor protein (LRBA). Phosphorylation levels of LRBA was nearly perfectly correlated with those of AQP2.
2022-07-23 | PXD033852 | Pride
Project description:This data provides evidence that elevation of cAMP levels has a dramatic effect on the transcriptome of yeast cells, with particular emphasis on mitochondrial function and the promotion of ROS production S. cerevisiae cells lacking the high affinity phosphodiesterase PDE2or both PDE2 and the PKA subunit TPK3 were grown for 24h in rich media in the presence of 4mM exogensously added cAMP. 8 samples.
2010-11-24 | E-GEOD-25541 | biostudies-arrayexpress
Project description:Intrinsic abnormalities in transplanted eutopic endometrium are believed to contribute to the pathogenesis of pelvic endometriosis. Herein, we investigated transcriptomic differences in human endometrial stromal fibroblasts (hESF) from women with (hESFendo) versus without (hESFnon-endo) endometriosis, in response to activation of the PKA pathway with 8-Br-cAMP. hESFnon-endo (n=4) and hESFendo (mild endometriosis, n=4) were isolated from eutopic endometrium and treated +/- 0.5mM 8-Br-cAMP for 96 hours. Purified total RNA was subjected to microarray analysis using the whole genome Gene 1.0 ST Affymetrix platform. 733 genes were regulated in cAMP-treated hESFnon-endo versus 172 genes in hESFendo, suggesting a blunted response to cAMP/PKA pathway activation in women with disease. Real-time PCR and ELISA validated the decreased expression of decidualization markers in hESFendo compared to hESFnon-endo. In the absence of disease, 8-Br-cAMP down-regulated progression through the cell-cycle due to a decrease in Cyclin D1, cyclin-dependent kinase 6 and cell division cycle 2, and an increase in cyclin-dependent kinase inhibitor 1A. However, cell cycle components in hESFendo were not responsive to 8-Br-cAMP, resulting in persistence of a proliferative phenotype. hESFendo treated with 8-Br-cAMP exhibited altered expression of immune response, extracellular matrix, cytoskeleton, and apoptosis genes. Changes in phosphodiesterase expression and activity were not different among experimental groups. Thus, eutopic hESF with increased proliferative potential may seed the pelvic cavity via retrograde menstruation and promote establishment, survival, and proliferation of endometriosis lesions, independent of hydrolysis of cAMP and likely due to an inherent abnormality in the PKA pathway in the presence of disease.
2009-12-19 | GSE17504 | GEO
Project description:Besozzi2012 - Oscillatory regimes in the Ras/cAMP/PKA pathway in S.cerevisiae
Mechanistic model of the Ras/cAMP/PKA in yeast S.cerevisiae. The Ras/cAMP/PKA pathway plays a major role in the regulation of metabolism, stress resistance and cell cycle progress and is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA). This model investigates the dynamics of the second messenger cAMP on Ras/cAMP/PKA pathway, to determine the effects of the feedback mechanisms on establising stable oscillatory regimes.
The model has been defined according to the stochastic formulation of chemical kinetics [Gillespie DT, 1977]
, which requires to specify the set of molecular species occurring in the pathway and their respective interactions, formally described as a set of biochemical reactions.
The volume considered for this system is 30fL; this value can be used to convert the model into the deterministic formulation.
This model is described in the article:
The role of feedback control mechanisms on the establishment of oscillatory regimes in the Ras/cAMP/PKA pathway in S. cerevisiae.
Besozzi D, Cazzaniga P, Pescini D, Mauri G, Colombo S, Martegani E.
EURASIP J Bioinform Syst Biol. 2012 Jul 20;2012(1):10.
Abstract:
In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway is involved in the regulation of cell growth and proliferation in response to nutritional sensing and stress conditions. The pathway is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA) on a few pivotal components of the pathway. In this article, we investigate the dynamics of the second messenger cAMP by performing stochastic simulations and parameter sweep analysis of a mechanistic model of the Ras/cAMP/PKA pathway, to determine the effects that the modulation of these feedback mechanisms has on the establishment of stable oscillatory regimes. In particular, we start by studying the role of phosphodiesterases, the enzymes that catalyze the degradation of cAMP, which represent the major negative feedback in this pathway. Then, we show the results on cAMP oscillations when perturbing the amount of protein Cdc25 coupled with the alteration of the intracellular ratio of the guanine nucleotides (GTP/GDP), which are known to regulate the switch of the GTPase Ras protein. This multi-level regulation of the amplitude and frequency of oscillations in the Ras/cAMP/PKA pathway might act as a fine tuning mechanism for the downstream targets of PKA, as also recently evidenced by some experimental investigations on the nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast cells.
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2013-09-11 | BIOMD0000000478 | BioModels
Project description:Cyclic AMP activates two downstream factors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC) and both downstream signalings induce syncytialization, cell fusion and the production of hCG and progesterone. We used microarray to identify novel transcription factors related to syncytialization in two cAMP signaling-stimulated BeWo cells.
2017-09-30 | GSE100095 | GEO
Project description:Using CRISPR/Cas9 to generate an hiPSC line with SETD1A haploinsufficiency and differentiating it into glutamatergic and GABAergic neurons, we found that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was predominantly defined by increased network burst frequency, whereas unchanged global firing activity. In individual neurons, this network phenotype was reflected functionally by increased synchronized synaptic inputs and structurally by increased somatodendritic complexity in both glutamatergic and GABAergic neurons. The transcriptome profile in SETD1A haploinsufficient neurons demonstrated perturbations in gene sets associated with schizophrenia, synaptic transmission, and glutamatergic synaptic function. In addition, transcriptomic data suggested cAMP/PKA pathway might be disturbed in SETD1A haploinsufficient networks, which was further verified by pharmacological experiments.
2021-07-23 | GSE180648 | GEO