Unraveling a mechanism driving poor-prognosis prostate cancer: overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118845 | GEO | 2019/05/01
REPOSITORIES: GEO
Similar Datasets
Project description:We assessed global gene expression changes in THP1 cells overexpressing inducible RRM2 non-degradable mutant versus empty vector upon doxycycline induction
2023-01-11 | GSE193769 | GEO
Project description:Human prostate cancer PC-3 cells stably overexpress RRM2. Overexpression of RRM2 were confirm by westernblot or qPCR. Transfected cells were prepared for RNA-seq.
2020-02-20 | GSE117923 | GEO
Project description:Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. However, emerging data suggests more diverse roles for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulin-independent mechanism of PC action in human autoimmunity B-cells were isolated from the peripheral blood of three adult donors and differentiated in vitro (see individual samples for culture conditions)
2016-07-22 | E-GEOD-75007 | biostudies-arrayexpress
Project description:There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells led to apoptosis and cell death in vitro and attenuated tumor growth in vivo in a xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further exploration of clinically used inhibitors of RNR as a therapeutic approach in treating this cancer.
2016-12-01 | GSE79641 | GEO
Project description:Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. However, emerging data suggests more diverse roles for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulin-independent mechanism of PC action in human autoimmunity
2016-07-22 | GSE75007 | GEO
Project description:The small intestinal crypts harbour secretory Paneth cells (PCs) which express bactericidal peptides that are crucial for maintaining intestinal homeostasis. Considering the diverse environmental conditions throughout the course of the small intestine, multiple subtypes of PCs are expected to exist. We applied single cell RNA-sequencing of PCs combined with deep bulk RNA-sequencing on PC populations of different small intestinal locations and discovered several expression-based PC clusters. Some of these are discrete and resemble tuft cell-like PCs, goblet cell (GC)-like PCs, PCs expressing stem cell markers, and atypical PCs. Other clusters are less discrete but appear to be derived from different locations along the intestinal tract and have environment-dictated functions such as food digestion and antimicrobial peptide production
2024-09-18 | GSE273983 | GEO
Project description:The p53R2 protein, a newly identified member of the ribonucleotide reductase family that provides nucleotides for DNA damage repair, is directly regulated by p53. We show that p53R2 is also regulated by a MEK2 (ERK kinase 2/MAP kinase kinase 2)-dependent pathway. Increased MEK1/2 phosphorylation by serum stimulation coincided with an increase in the RNR activity in U2OS and H1299 cells. The inhibition of MEK2 activity, either by treatment with a MEK inhibitor or by transfection with MEK2 siRNA, dramatically decreased the serum-stimulated RNR activity. Moreover, p53R2 siRNA, but not R2 siRNA, significantly inhibits serum-stimulated RNR activity, indicating that p53R2 is specifically regulated by a MEK2-dependent pathway. Co-immunoprecipitation analyses revealed that the MEK2 segment comprising amino acids 65-171 is critical for p53R2-MEK2 interaction, and the binding domain of MEK2 is required for MEK2-mediated increased RNR activity. Phosphorylation of MEK1/2 was greatly augmented by ionizing radiation, and RNR activity was concurrently increased. Ionizing radiation-induced RNR activity was markedly attenuated by transfection of MEK2 or p53R2 siRNA, but not R2 siRNA. These data show that MEK2 is an endogenous regulator of p53R2 and suggest that MEK2 may associate with p53R2 and upregulate its activity.
| S-EPMC3466523 | biostudies-literature
Project description:Paneth cells (PCs) are post-mitotic secretory cells of the small intestine that produce antimicrobials, growth factors, and cytokines. Multiple diseases have been linked to alterations in PC function. Past studies of PCs have relied on in vivo models, and limited in vitro models, including organoids. While useful, whether the in vitro models recapitulate in vivo biology is an important, yet unanswered question. Here, we present a bona fide in vitro PC-enriched population derived via chemically-induced (CI) differentiation of primary murine adult stem cells. We define the identity of PCs in our system and compare to PCs of established organoid systems and those found in vivo. Importantly, we demonstrate stimulant-induced and microbe-responsive antimicrobial function of our CI-PCs – hallmark functions of PCs in vivo. Thus, we define and produce the most physiologically-relevant in vitro PC population to date, providing a superior tool to study cellular development, host-microbe interactions, and inflammatory disease.
2018-04-02 | GSE100274 | GEO
Project description:Ribonucleotide reductases (RNRs) use a conserved radical-based mechanism to catalyze the conversion of ribonucleotides to deoxyribonucleotides. Within the RNR family, class Ib RNRs are notable for being largely restricted to bacteria, including many pathogens, and for lacking an evolutionarily mobile ATP-cone domain that allosterically controls overall activity. In this study, we report the emergence of a distinct and unexpected mechanism of activity regulation in the sole RNR of the model organism Bacillus subtilis. Using a hypothesis-driven structural approach that combines the strengths of small-angle X-ray scattering (SAXS), crystallography, and cryo-electron microscopy (cryo-EM), we describe the reversible interconversion of six unique structures, including a flexible active tetramer and two inhibited helical filaments. These structures reveal the conformational gymnastics necessary for RNR activity and the molecular basis for its control via an evolutionarily convergent form of allostery.
| S-EPMC6572854 | biostudies-literature
Project description:In vivo antigen (Ag)-induced differentiation of B lymphocytes into plasma cells (PCs) takes place in extra-follicular foci and germinal centers of the secondary lymphoid organs (SLOs). Most of these SLO PCs are short-living and only relatively few PCs, characterized by secreting high-affinity antibodies (Ab), travel through the circulation and finally home in specialized survival niches of the bone marrow (BM) and, at a lesser extent, in the SLOs, where they become long-living Ab-secreting PCs. Initially, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between human circulating Ag-induced PCs in comparison with tonsil and BM PCs distinctively regulate genes involved in cell proliferation. Now, moreover, to characterize further the B-cell transition into PC, transcriptomes from human naïve B lymphocytes were also included in the analysis, and genes showing significant changes in the comparison between B lymphocytes and every of the three PC subsets were selected as the PC signature.
2017-09-12 | GSE81589 | GEO