期刊
BIOCHEMICAL PHARMACOLOGY
卷 77, 期 3, 页码 397-411出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2008.09.041
关键词
TNF alpha; NF-kappa B; GGT; Sp1; Curcumin; Inflammation
资金
- Recherche Cancer et Sang foundation
- Recherches Scientifiques Luxembourg association
- Government of Luxembourg
- Action Lions Vaincre le Cancer
- Clayton Foundation for Research
- National Institutes of Health
gamma-Glutamyltransferase (GGT) cleaves the gamma-glutamyl moiety of glutathione (GSH), an endogenous antioxidant, and is involved in mercapturic acid metabolism and in cancer drug resistance when overexpressed. Moreover, GGT converts leukotriene (LT) C4 into LTD4 implicated in various inflammatory pathologies. So far the effect of inflammatory stimuli on regulation of GGT expression and activity remained to be addressed. We found that the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) induced GGT promoter transactivation, mRNA and protein synthesis, as well as enzymatic activity. Remicade, a clinically used anti-TNF alpha antibody, small interfering RNA (siRNA) against p50 and p65 nuclear factor-kappaB (NF-kappa B) isoforms, curcumin, a well characterized natural NF-kappa B inhibitor, as well as a dominant negative inhibitor of kappaB alpha (I kappa B alpha), prevented GGT activation at various levels, illustrating the involvement of this signaling pathway in TNF alpha-induced stimulation. Over-expression of receptor of TNF alpha-1 (TNFR1), TNFR-associated factor-2 (TRAF2), TNFR-1 associated death domain (TRADD), dominant negative (DN) I kappa B alpha or NF-kappa B p65 further confirmed GGT promoter activation via NF-kappa B. Linker insertion mutagenesis of 536 bp of the proximal GGT promoter revealed NF-kappa B and Sp1 binding sites at -110 and -78 relative to the transcription start site, responsible for basal GGT transcription. Mutation of the NF-kappa B site located at -110 additionally inhibited TNF alpha-induced promoter induction. Chromatin immunoprecipitation (ChIP) assays confirmed mutagenesis results and further demonstrated that TNF alpha treatment induced in vivo binding of both NF-kappa B and Sp1, explaining increased GGT expression, and led to RNA polymerase II recruitment under inflammatory conditions. (C) 2008 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据