Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE232359 | GEO | 2024/11/11
REPOSITORIES: GEO
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Project description:Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis
| PRJNA971725 | ENA
Project description:Although the Mnks have been known for >15 years, their roles in the regulation of protein synthesis have remained obscure. Here we explore how BDNF stimulates protein synthesis in cortical neurons. Using a combination of pharmacological and genetic approaches, we show that this effect depends on MEK/ERK signaling and on the downstream kinase, Mnk1, which phosphorylates eIF4E. Translation initiation is mediated by the interaction of eIF4E with the m7GTP cap of mRNA and with eIF4G. The latter interaction is inhibited by the interactions of eIF4E with partner proteins such as CYFIP1, which together with its partner, FMRP acts as a translational repressor. We find that BDNF induces the release of CYFIP1 from eIF4E, and that this depends on Mnk1. Finally, using a novel combination of BONCAT and SILAC, we identify the a subset of proteins whose synthesis is upregulated by BDNF signalling via Mnk1 in neurons. The This subset of Mnk1-sensitive proteins are enriched for functions involved in neurotransmission and synaptic plasticity. Additionally, we find significant overlap between our subset of Mnk1 Mnk1-sensitive proteins and proteins encoded by known FMRP-binding mRNAs. Taken together, our data implicate Mnk1 as a key component of BDNF-mediated translational regulation in neurons.
2014-11-06 | PXD001074 | Pride
Project description:AimsEpidemiological studies report an inverse association between plant-derived dietary ?-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model.Methods and resultsEight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-?, interleukin-4, and tumour necrosis factor ? (TNF?) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n-3 long chain fatty acids (LC n-3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNF?. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA.ConclusionDietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n-3 FA.
| S-EPMC3195262 | biostudies-literature
Project description:Tumors were harvested at day 24 post tumor cell engraftment and dissociated into single-cell suspensions. RFP-positive 4T1 cells were isolated by fluorescence-activated cell sorting (FACS). RNA was extracted using the RNeasy Mini Kit. Three independent RNA preparations from cultured 4T1-Luc2-RFP cells and FACS-isolated 4T1-Luc2-RFP cells were submitted for RNA sequencing analysis.
2019-04-02 | GSE129106 | GEO
Project description:While the administration of anti-CD154 mAbs in mice validated the CD40-CD154 pathway as a target against inflammatory disorders, this approach caused thromboembolism in humans (unrelated to CD40 inhibition) and is expected to predispose to opportunistic infections. There is a need for alternative approaches to inhibit CD40 that avoid these complications. CD40 signals through TRAF2,3 and TRAF6-binding sites. Given that CD40-TRAF6 is the pathway that stimulates responses key for cell-mediated immunity against opportunistic pathogens, we examined the effects of pharmacologic inhibition of CD40-TRAF2,3 signaling. We used a model of ischemia/reperfusion (I/R)-induced retinopathy, a CD40-driven inflammatory disorder. Intravitreal administration of a cell-penetrating CD40-TRAF2,3 blocking peptide impaired ICAM-1 upregulation in retinal endothelial cells and CXCL1 upregulation in endothelial and Müller cells. The peptide reduced leukocyte infiltration, upregulation of NOS2/COX-2/TNF-α/IL-1β, and ameliorated neuronal loss, effects that mimic those observed after I/R in Cd40-/- mice. While a cell-penetrating CD40-TRAF6 blocking peptide also diminished I/R-induced inflammation, this peptide (but not the CD40-TRAF2,3 blocking peptide) impaired control of the opportunistic pathogen Toxoplasma gondii in the retina. Thus, inhibition of the CD40-TRAF2,3 pathway is a novel and potent approach to reduce CD40-induced inflammation, while likely diminishing the risk of opportunistic infections that would otherwise accompany CD40 inhibition.
| S-EPMC8101361 | biostudies-literature
Project description:Insufficient sleep is a global public health problem resulting in catastrophic accidents, increased mortality, and hundreds of billions of dollars in lost productivity. Yet the effect of sleep deprivation (SD) on decision making and performance is often underestimated by fatigued individuals and is only beginning to be understood by scientists. The deleterious impact of SD is frequently attributed to lapses in vigilant attention, but this account fails to explain many SD-related problems, such as loss of situational awareness and perseveration. Using a laboratory study protocol, we show that SD individuals can maintain information in the focus of attention and anticipate likely correct responses, but their use of such a top-down attentional strategy is less effective at preventing errors caused by competing responses. Moreover, when the task environment requires flexibility, performance under SD suffers dramatically. The impairment in flexible shifting of attentional control we observed is distinct from lapses in vigilant attention, as corroborated by the specificity of the influence of a genetic biomarker, the dopaminergic polymorphism DRD2 C957T. Reduced effectiveness of top-down attentional control under SD, especially when conditions require flexibility, helps to explain maladaptive performance that is not readily explained by lapses in vigilant attention.
| S-EPMC5700060 | biostudies-literature
Project description:P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action.
| S-EPMC7196789 | biostudies-literature
Project description:Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (trap) to comprehensively characterize up- and down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.
2018-08-01 | GSE113941 | GEO
Project description:OBJECTIVE:Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). DESIGN:Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1-6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy. RESULTS:Tumour-infiltrating CD11b+CD33+HLA-DR- MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR- MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-?B (NF-?B) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-?B-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-?B/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon ?+tumour necrosis factor-?+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC. CONCLUSION:Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
| S-EPMC5961939 | biostudies-literature
Project description:Human myxovirus resistance protein 2 (huMxB) has been shown to be a determinant type I interferon (IFN)-induced host factor involved in the inhibition of human immunodeficiency virus type 1 (HIV-1) as well as many other primate lentiviruses. This blocking occurs after the reverse transcription of viral RNA and ahead of integration into the host DNA, which is closely connected to the ability of the protein to bind the viral capsid. To date, Mx2s derived from nonprimate animals have shown no capacity for HIV-1 suppression. In this study, we examined the restrictive effect of equine Mx2 (eqMx2) on both equine infectious anemia virus (EIAV) and HIV-1 and investigated possible mechanisms for its specific function. We demonstrated that IFN-?/? upregulates the expression of eqMx2 in equine monocyte-derived macrophages (eMDMs). The overexpression of eqMx2 significantly suppresses the replication of EIAV, HIV-1, and simian immunodeficiency viruses (SIVs) but not that of murine leukemia virus (MLV). The knockdown of eqMx2 transcription weakens the inhibition of EIAV replication by type I interferon. Interestingly, data from immunofluorescence assays suggest that the subcellular localization of eqMx2 changes following virus infection, from being dispersed in the cytoplasm to being accumulated at the nuclear envelope. Furthermore, eqMx2 blocks the nuclear uptake of the proviral genome by binding to the viral capsid. The N-terminally truncated mutant of eqMx2 lost the ability to bind the viral capsid as well as the restriction effect for lentiviruses. These results improve our understanding of the Mx2 protein in nonprimate animals.IMPORTANCE Previous research has shown that the antiviral ability of Mx2s is confined to primates, particularly humans. EIAV has been shown to be insensitive to restriction by human MxB. Here, we describe the function of equine Mx2. This protein plays an important role in the suppression of EIAV, HIV-1, and SIVs. The antiviral activity of eqMx2 depends on its subcellular location as well as its capsid binding capacity. Our results showed that following viral infection, eqMx2 changes its original cytoplasmic location and accumulates at the nuclear envelope, where it binds to the viral capsid and blocks the nuclear entry of reverse-transcribed proviral DNAs. In contrast, huMxB does not bind to the EIAV capsid and shows no EIAV restriction effect. These studies expand our understanding of the function of the equine Mx2 protein.
| S-EPMC6146692 | biostudies-literature