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  • Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway. 25267977

    8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. In this study, we proposed that the mechanistic link between OGG1-BER and proinflammatory gene expression is OGG1's guanine nucleotide exchange factor activity, acquired after interaction with the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we used BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pulldown, reporter and Comet assays, small interfering RNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-initiated repair of oxidatively damaged DNA is a prerequisite for GDP → GTP exchange, KRAS-GTP-driven signaling via MAP kinases and PI3 kinases and mitogen-stress-related kinase-1 for NF-κB activation, proinflammatory chemokine/cytokine expression, and inflammatory cell recruitment to the airways. Mice deficient in OGG1-BER showed significantly decreased immune responses, whereas a lack of other Nei-like DNA glycosylases (i.e., NEIL1 and NEIL2) had no significant effect. These data unveil a previously unidentified role of OGG1-driven DNA BER in the generation of endogenous signals for inflammation in the innate signaling pathway.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-1072
    Nombre del producto:
    Anti-Ras Antibody, (K-, H-, N-), clone 9A11.2

  • Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome duplication. 17015463

    Nucleophosmin (NPM)/B23 has been implicated in the regulation of centrosome duplication. NPM/B23 localizes between two centrioles in the unduplicated centrosome. Upon phosphorylation on Thr(199) by cyclin-dependent kinase 2 (CDK2)/cyclin E, the majority of centrosomal NPM/B23 dissociates from centrosomes, but some NPM/B23 phosphorylated on Thr(199) remains at centrosomes. It has been shown that Thr(199) phosphorylation of NPM/B23 is critical for the physical separation of the paired centrioles, an initial event of the centrosome duplication process. Here, we identified ROCK II kinase, an effector of Rho small GTPase, as a protein that localizes to centrosomes and physically interacts with NPM/B23. Expression of the constitutively active form of ROCK II promotes centrosome duplication, while down-regulation of ROCK II expression results in the suppression of centrosome duplication, especially delaying the initiation of centrosome duplication during the cell cycle. Moreover, ROCK II regulates centrosome duplication in its kinase and centrosome localization activity-dependent manner. We further found that ROCK II kinase activity is significantly enhanced by binding to NPM/B23 and that NPM/B23 acquires a higher binding affinity to ROCK II upon phosphorylation on Thr(199). Moreover, physical interaction between ROCK II and NPM/B23 in vivo occurs in association with CDK2/cyclin E activation and the emergence of Thr(199)-phosphorylated NPM/B23. All these findings point to ROCK II as the effector of the CDK2/cyclin E-NPM/B23 pathway in the regulation of centrosome duplication.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-443

  • Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E2 and 15-deoxy-Δ(12,14)-PGJ2. 22096605

    Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E(2), PGD(2) and its dehydration end product 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE(2) directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD(2) and 15d-PGJ(2) in the absence or presence of PGE(2) on IL-6 synthesis in human chondrocytes have yet to be determined. It is believed that dysregulated overproduction of IL-6 is responsible for the systemic inflammatory manifestations and abnormal laboratory findings in RA patients.Using the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE(2) and PGD(2)/15d-PGJ(2) exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE(2) stimulates Toll-like receptor 4 (TLR4) synthesis, which is in turn responsible for the activation of the ERK1/2, PI3K/Akt and PKA/CREB pathways that phosphorylate the NF-κB p65 subunit leading to NF-κB activation. Binding of the activated NF-κB p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD(2) or 15d-PGJ(2) concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE(2)-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-κB-dependent IL-6 synthesis in chondrocytes.We have delineated the signaling cascade by which PGE(2) and PGD(2)/15d-PGJ(2) exert opposing effects on IL-6 synthesis in human chondrocytes. Elucidation of the molecular pathway of IL-6 synthesis and secretion by chondrocytes will provide insights for developing strategies to reduce inflammation and pain in RA patients.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-371
    Nombre del producto:
    EZ-ChIP™