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• W2034007475 endingPage "26299" @default.
• W2034007475 startingPage "26287" @default.
• W2034007475 abstract "Ras farnesyltransferase inhibitor (FTI) exhibit antiproliferative and antiangiogenic effects through a mechanism that is poorly understood. Because of the known role of Ras in the activation of transcription factor NF-κB and because NF-κB-regulated genes can control cell survival and angiogenesis, we postulated that FTI mediates its effects in part by modulating NF-κB activation. Therefore, in the present study we investigated the effect of FTI, SCH 66336, on NF-κB and NF-κB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. We demonstrate by DNA-binding assay that NF-κB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, cigarette smoke, okadaic acid, and H2O2 was completely suppressed by SCH 66336; the suppression was not cell type-specific. This FTI suppressed the activation of IκBα kinase (IKK), thus abrogating the phosphorylation and degradation of IκBα. Additionally, TNF-activated Ras and SCH 66336 inhibited the activation. Also, overexpression of Ras (V12) enhanced TNF-induced NF-κB activation, and adenoviral dominant-negative Ras (N17) suppressed the activation, thus suggesting the critical role of Ras in TNF signaling. SCH 66336 also inhibited the NF-κB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-κB. The TNF-induced NF-κB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP1, IAP2, XIAP, Bcl-2, Bfl-1/A1, TRAF1, and FLIP were all down-regulated by SCH 66336, which potentiated apoptosis induced by TNF and doxorubicin. Overall, our results indicate that SCH 66336 inhibited activation of NF-κB and NF-κB-regulated gene expressions induced by carcinogens and inflammatory stimuli, which may provide a molecular basis for the ability of SCH 66336 to suppress proliferation and angiogenesis." @default.
• W2034007475 created "2016-06-24" @default.
• W2034007475 creator A5048675624 @default.
• W2034007475 creator A5058282779 @default.
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• W2034007475 date "2004-06-01" @default.
• W2034007475 modified "2023-10-13" @default.
• W2034007475 title "Protein Farnesyltransferase Inhibitor (SCH 66336) Abolishes NF-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli Leading to Suppression of NF-κB-regulated Gene Expression and Up-regulation of Apoptosis" @default.
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• W2034007475 doi "https://doi.org/10.1074/jbc.m400963200" @default.
• W2034007475 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/15090542" @default.
• W2034007475 hasPublicationYear "2004" @default.
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