PRL2 serves as a negative regulator in cell adaptation to oxidative stress.
Ontology highlight
ABSTRACT:
SUBMITTER: Du X
PROVIDER: S-EPMC6884919 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Phagocytosis and oxidative burst are two major effector arms of innate immunity. Although it is known that both are activated by Toll-like receptors (TLRs) and Rac GTPases, how their strengths are controlled in quiescent and TLR-activated cells is not clear. We report here that TIPE2 (TNFAIP8L2) serves as a negative regulator of innate immunity by linking TLRs to Rac. TLRs control the expression levels of TIPE2, which in turn dictates the strengths of phagocytosis and oxidative burst by binding to and blocking Rac GTPases. Consequently, TIPE2 knockout cells have enhanced phagocytic and bactericidal activities and TIPE2 knockout mice are resistant to bacterial infection. Thus, TIPE2 sets the strengths of phagocytosis and oxidative burst and may be targeted to effectively control infections.
| S-EPMC3458374 | biostudies-literature
Project description:Artemis is a multifunctional phospho-protein with roles in V(D)J recombination, repair of double-strand breaks by nonhomologous end-joining and regulation of cell-cycle checkpoints after DNA damage. Here, we describe a new function of Artemis as a negative regulator of p53 in response to oxidative stress in both primary cells and cancer cell lines. We show that depletion of Artemis under typical culture conditions (21% oxygen) leads to a spontaneous phosphorylation and stabilization of p53, and resulting cellular G1 arrest and apoptosis. These effects are suppressed by co-depletion of DNA-PKcs, but not ATM, indicating that Artemis is an inhibitor of DNA-PKcs-mediated stabilization of p53. Culturing of cellsat 3% oxygen or treatment with an antioxidant abrogated p53 stabilization, indicating that oxidative stress is the responsible cellular stimulus. Treatment with ionizing radiation or hydrogen peroxide did not cause activation of this signaling pathway, whereas inhibitors of mitochondrial electron transport were effective in reducing its activation. In addition, we show that p53-inducible genes involved in reducing reactive oxygen species are upregulated by Artemis depletion. These findings indicate that Artemis and DNA-PKcs participate in a new, signaling pathway to modulate p53 function in response to oxidative stress produced by mitochondrial respiration.
| S-EPMC2692457 | biostudies-literature
Project description:Background:Human positive cofactor 4 (PC4) was initially characterized as a multifunctional transcriptional cofactor, but its role in skin wound healing is still unclear. The purpose of this study was to explore the role of PC4 in skin wound healing through PC4 knock-in mouse model. Methods:A PC4 knock-in mouse model (PC4+/+) with a dorsal full-thickness wound was used to investigate the biological functions of PC4 in skin wound healing. Quantitative PCR, Western blot analysis and immunohistochemistry were performed to evaluate the expression of PC4; Sirius red staining and immunofluorescence were performed to explore the change of collagen deposition and angiogenesis. Proliferation and apoptosis were detected using Ki67 staining and TUNEL assay. Primary dermal fibroblasts were isolated from mouse skin to perform cell scratch experiments, cck-8 assay and colony formation assay. Results:The PC4+/+ mice were fertile and did not display overt abnormalities but showed an obvious delay in cutaneous healing of dorsal skin. Histological staining showed insufficient re-epithelialization, decreased angiogenesis and collagen deposition, increased apoptosis and decreased cell proliferation in PC4+/+ skin. Our data also showed decreased migration rate and proliferation ability in cultured primary fibroblasts from PC4+/+ mice in vitro. Conclusions:This study suggests that PC4 might serve as a negative regulator of skin wound healing in mice.
| S-EPMC7198317 | biostudies-literature
Project description:CD160 and BTLA both bind to herpes virus entry mediator. Although a negative regulatory function of BTLA in natural killer T (NKT) cell activation has been reported, whether CD160 is also involved is unclear. By analyzing CD160-/- mice and mixed bone marrow chimeras, we show that CD160 is not essential for NKT cell development. However, CD160-/- mice exhibit severe liver injury after in vivo challenge with α-galactosylceramide (α-GalCer). Moreover, CD160-/- mice are more susceptible to Concanavalin A challenge, and display elevated serum AST and ALT levels, hyperactivation of NKT cells, and enhanced IFN-γ, TNF, and IL-4 production. Lastly, inhibition of BTLA by anti-BTLA mAb aggravates α-GalCer-induced hepatic injury in CD160-/- mice, suggesting that both CD160 and BTLA serve as non-overlapping negative regulators of NKT cells. Our data thus implicate CD160 as a co-inhibitory receptor that delivers antigen-dependent signals in NKT cells to dampen cytokine production during early innate immune activation.
| S-EPMC6646315 | biostudies-literature
Project description:We show that thiols in the 4-cysteine zinc-finger motif of DksA, an RNA polymerase accessory protein known to regulate the stringent response, sense oxidative and nitrosative stress. Hydrogen peroxide- or nitric oxide (NO)-mediated modifications of thiols in the DksA 4-cysteine zinc-finger motif release the metal cofactor and drive reversible changes in the ?-helicity of the protein. Wild-type and relA spoT mutant Salmonella, but not isogenic dksA-deficient bacteria, experience the downregulation of r-protein and amino acid transport expression after NO treatment, suggesting that DksA can regulate gene expression in response to NO congeners independently of the ppGpp alarmone. Oxidative stress enhances the DksA-dependent repression of rpsM, while preventing the activation of livJ and hisG gene transcription that is supported by reduced, zinc-bound DksA. The inhibitory effects of oxidized DksA on transcription are reversible with dithiothreitol. Our investigations indicate that sensing of reactive species by DksA redox active thiols fine-tunes the expression of translational machinery and amino acid assimilation and biosynthesis in accord with the metabolic stress imposed by oxidative and nitrosative stress. Given the conservation of Cys(114) , and neighbouring hydrophobic and charged amino acids in DksA orthologues, phylogenetically diverse microorganisms may use the DksA thiol switch to regulate transcriptional responses to oxidative and nitrosative stress.
| S-EPMC4053250 | biostudies-literature
Project description:Caloric restriction extends lifespan, an effect once thought to involve attenuation of reactive oxygen species (ROS) generated by aerobic metabolism. However, recent evidence suggests that caloric restriction may in fact raise ROS levels, which in turn provides protection from acute doses of oxidant through a process called adaptation. To shed light on the molecular mechanisms of adaptation, we designed a series of genome-wide deletion fitness screens to identify genes involved in adaptation to hydrogen peroxide.
2009-04-23 | GSE12733 | GEO
Project description:Pathogenic Leptospira spp. are the causative agents of the zoonotic disease leptospirosis. During infection, Leptospira are confronted with deadly reactive oxygen species (ROS). Withstanding ROS produced by the host innate immunity is an important strategy evolved by pathogenic Leptospira for persisting in and colonizing hosts. The peroxide stress regulator, PerR, represses genes involved in ROS defenses in L. interrogans. We have performed RNA sequencing in WT and perR mutant strains to characterize the L. interrogans adaptive response to hydrogen peroxide. We showed that Leptospira solicit three main peroxidase machineries (catalase, cytochrome C peroxidase and peroxiredoxin) and heme to adapt to peroxide stress as well as canonical chaperones of the heat shock response, and DNA repair. Determining the PerR regulon allowed to identify the PerR-dependent mechanisms of the peroxide adaptive response and has revealed a regulatory network involving other transcriptional regulators, two-component systems and sigma factors as well as non-coding RNAs that putatively orchestrate, in concert with PerR, this adaptive response. Our findings provide comprehensive insight into the mechanisms required by pathogenic Leptospira to overcome infection-related oxidants. This will participate in framing future hypothesis-driven studies to identify and decipher novel virulence mechanisms.
2020-09-22 | GSE140019 | GEO
Project description:Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homoeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
| S-EPMC11303387 | biostudies-literature
Project description:Plant and cyanobacteria can perceive signals from soluble sugar and reactive oxygen species (ROS) and then coordinate gene expression under stress acclimation, but the underlying mechanism remains unclear. In this study, we found that the transcriptional factor PrqR (Slr0895) in Synechocystis can perceive signals from ROS generated after shifting from prolonged darkness with glucose into high-light. The deletion mutant (DprqR) showed increased growth rate and decreased ROS content, whereas the complementary strain (CprqR) restored the growth characteristics, phenotypes and ROS status of WT, thereby establishing PrqR as a negative regulator of ROS.LC/GC-MS-based metabolic profiling also showed active ROS mitigation in DprqR mutant. Further study by qRT-PCR, ChIP-PCR and deletion of both prqR and prqA (DprqR-DprqA mutant) revealed that PrqR exerts this negative regulation of ROS removal by controlling the expression of sodB and prqA (slr0896). Furthermore, PrqR also found to control glucose metabolism by regulating a positive regulator of glucose metabolism, sigE, and its regulons. Results suggest that PrqR was involved in perceiving signals from ROS under physiological condition, as well as in regulating stress removal and glucose metabolism.
| S-EPMC5007503 | biostudies-literature
Project description:BackgroundInterleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation.ObjectiveThe goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium.MethodsComplementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules.ResultsHuman bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs.ConclusionsThe balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.
| S-EPMC5591045 | biostudies-literature