Novel mechanism of inhibition of nuclear factor-kappa B DNA-binding activity by diterpenoids isolated from Isodon rubescens

doi:10.1124/mol.105.012765

	Novel mechanism of inhibition of nuclear factor-kappa B DNA-binding activity by diterpenoids isolated from Isodon rubescens
	Leung, CH ; Grill, SP ; Lam, W ; Han, QB ; Sun, HD; Cheng, YC
	2005-08-01
发表期刊	MOLECULAR PHARMACOLOGY
卷号	68 期号:2 页码:286-297
摘要	The development of specific inhibitors that can block nuclear factor-kappa B (NF-kappa B) activation is an approach for the treatment of cancer, autoimmune, and inflammatory diseases. Several diterpenoids, oridonin, ponicidin, xindongnin A, and xindongnin B were isolated from the herb Isodon rubescens. These compounds were found to be potent inhibitors of NF-kappa B transcription activity and the expression of its downstream targets, cyclooxygenase-2 and inducible nitric-oxide synthase. The mechanisms of action of the diterpenoids against NF-kappa B are similar, but significant differences were also identified. All of the diterpenoids directly interfere with the DNA-binding activity of NF-kappa B to its response DNA sequence. Oridonin and ponicidin have an additional impact on the translocation of NF-kappa B from the cytoplasm to nuclei without affecting I kappa B-alpha phosphorylation and degradation. The effect of these compounds on the interaction of NF-kappa B with consensus DNA sequences is unique. Different inhibitory effects were observed when NF-kappa B bound to various DNA sequences. Both p65/p65 and p50/p50 homodimers, as well as p65/p50 heterodimer association with their responsive DNA, were inhibited. Kinetic studies on NF-kappa B-DNA interaction indicate that the diterpenoids decrease the B-max (app) but have no effect on K-d app. This suggests that this class of compounds interacts with both p65 and p50 subunits at a site other than the DNA binding site and subsequently modulates the binding affinity of the transcription factor toward DNA with different NF-kappa B binding sequences. The diterpenoid structure could therefore serve as a scaffold for the development of more potent and selective NF-kappa B inhibitors that target regulated gene transcription.
DOI	10.1124/mol.105.012765
收录类别	SCI
语种	英语
WOS记录号	WOS:000230549900005
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/24792
专题	植物化学与西部植物资源持续利用国家重点实验室
作者单位	1.Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA 2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W China, Beijing 100864, Peoples R China
推荐引用方式 GB/T 7714	Leung, CH,Grill, SP,Lam, W,et al. Novel mechanism of inhibition of nuclear factor-kappa B DNA-binding activity by diterpenoids isolated from Isodon rubescens[J]. MOLECULAR PHARMACOLOGY,2005,68(2):286-297.
APA	Leung, CH,Grill, SP,Lam, W,Han, QB,Sun, HD,&Cheng, YC.(2005).Novel mechanism of inhibition of nuclear factor-kappa B DNA-binding activity by diterpenoids isolated from Isodon rubescens.MOLECULAR PHARMACOLOGY,68(2),286-297.
MLA	Leung, CH,et al."Novel mechanism of inhibition of nuclear factor-kappa B DNA-binding activity by diterpenoids isolated from Isodon rubescens".MOLECULAR PHARMACOLOGY 68.2(2005):286-297.

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