کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1964899 | 1058632 | 2007 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
TNF-α-induced NF-κB/RelA Ser276 phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway
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کلمات کلیدی
PKAcNF-κBMSK-1NACGAPDHIL-8RNA polymerase II - آرانای پلیمراز II CBP/p300 - CBP / p300DMSO - DMSOROS - ROSchromatin immunoprecipitation - ایمن سازی کروماتینInterleukin-8 - اینترلوکین -8Dimethyl sulfoxide - دیمتیل سولفواکسیدRelA - رالاPhosphorylation - فسفریلاسیونN-acetyl cysteine - نیتستیل سیستئینPol II - پل دومEnhanceosome - پیشرفتهCHiP - چیپreactive oxygen species. - گونه های اکسیژن واکنش پذیر.Reactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
Tumor necrosis factor-α (TNF-α) is a potent mediator of inflammation, inducing expression of a gene network mediated by NF-κB. Previously we found that TNF-α-induced reactive oxygen species (ROS) production is required for NF-κB action because antioxidants inhibited TNF-α-inducible IL-8 expression without affecting its nuclear translocation. Here, we further investigated this ROS pathway controlling NF-κB/RelA dependent gene expression. We observed that TNF-α enhanced ROS production â¼Â 2-fold 20 min after stimulation and significantly increased oxidative DNA damage (8-oxoguanine lesions) over controls. Treatment with chemically unrelated antioxidants specifically inhibited expression of TNF-inducible NF-κB-dependent genes without producing detectable cytotoxicity or affecting GAPDH expression. We found that TNF-α-induced NF-κB/RelA Ser276 phosphorylation, a modification critical for its transcriptional activity, was inhibited by abrogation of the ROS signaling pathway, whereas NF-κB/RelA Ser536 phosphorylation was not. Interestingly, antioxidant treatment selectively inhibited TNF-α-induced catalytic activity of cAMP dependent protein kinase A (PKAc) but not mitogen-stress related kinase-1 (MSK1), kinases known to phosphorylate RelA at Ser276. Using PKAc inhibitors and siRNA mediated PKAc knockdown, TNF-α-induced Ser276 phosphorylation and IL-8 expression were both significantly reduced, indicating PKAc is required for RelA Ser276 phosphorylation. Consistently, a site mutation of Rel A (Ser276 to Ala) in RelA-deficient embryonic fibroblasts failed to activate IL-8 Luciferase activity in response to TNF-α. Furthermore, TNF-α-inducible NF-κB/RelA interaction with the co-activator CBP/p300, essential for enhanceosome formation, was attenuated by antioxidant treatment. Using chromatin immunoprecipitation assay (ChIP), we observed that recruitment of p300 and RNA polymerase II (Pol II) to the IL-8 promoter was also abrogated by antioxidant. These results indicate that the ROS-mediated TNF-α-induced IL-8 transcription is regulated by NF-κB/RelA phosphorylation at the critical Ser276 residue by PKAc, resulting in stable enhanceosome formation on target genes. These studies provide insight into a novel antioxidant-sensitive pathway that can be targeted to inhibit NF-κB-mediated inflammation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 19, Issue 7, July 2007, Pages 1419-1433
Journal: Cellular Signalling - Volume 19, Issue 7, July 2007, Pages 1419-1433
نویسندگان
Mohammad Jamaluddin, Shaofei Wang, Istvan Boldogh, Bing Tian, Allan R. Brasier,