REGULATION OF GENE EXPRESSION BY NO/CGMP
NO/CGMP 对基因表达的调节
基本信息
- 批准号:6019266
- 负责人:
- 金额:$ 22.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-09-01 至 2003-08-31
- 项目状态:已结题
- 来源:
- 关键词:affinity chromatography biological signal transduction cGMP dependent protein kinase chimeric proteins cyclic GMP enzyme activity enzyme mechanism enzyme substrate genetic enhancer element genetic promoter element genetic regulatory element immunofluorescence technique nitric oxide nucleic acid sequence oligonucleotides site directed mutagenesis transcription factor tumor necrosis factor alpha yeast two hybrid system
项目摘要
DESCRIPTION (Investigator's Abstract): The nitric oxide
(NO)cGMP/cGMP-dependent protein kinase (G-kinase) signal transduction
pathway is important for the regulation of many physiological and
pathophysiological processes, e.g., in the cardiovascular system it is a
major determinant of smooth muscle cell, endothelial cell and platelet
functions and is implicated in the development of hypertension and
atherosclerosis. However, compared to cAMP-dependent protein kinase, little
is known about the downstream effects of G-kinase activation. The
investigators found that G-kinase regulates gene expression: in response to
NO or cGMP, the kinase translocates to the nucleus, induces phosphorylation
of CREB-related proteins and activates the fos, junB and TNF-alpha
promoters. Preliminary data suggest that G-kinase transactivates these
promoters through similar cis-acting elements recognized by transcription
factors of the AP-1 (Fos-Jun), CRE- and CCAAT-enhancer binding protein
families and that subcellular localization and biological activity of the
kinase is regulated by specific anchoring proteins. The speciic aims of
this proposal are: (1) to define DNA sequences of NO/cGMP-response elements
(NGREs): (II) to identify transcription factors targeted by
NO/cGMP/G-kinase; and (III) to identify key substrates and cytoplasmic or
nuclear anchoring proteins which bind to G-kinase. NGREs will be defined by
deletion and site-directed mutagenesis of putative enhancer elements in the
fos and TNF-alpha promoters. Transcription factors targeted by NO/cGMP will
be identified in transactivation studies using Ga14-fusion products and
dominant negative mutants of candidate transcription factors as well as in
DNA binding studies and DNA affinity chromatography using
oligodeoxynucleotides encoding NGREs. Protein interaction cloning will be
employed to identify proteins interacting with G-kinase and the effect of
these proteins on subcellular localization and function of G-kinase will be
tested. The widespread importance of NO as a signaling molecule has been
recognized recently; the studies proposed in this grant application should
provide new insights into the mechanism of action of NO and cGMP in
mammalian cells. Since pharmacological manipulation of the NO/cGMP signal
transduction pathway offers therapeutic potential for a wide variety of
human diseases, a better understanding of the long-term downstream effects
of NO and cGMP is urgently needed.
描述(研究人员摘要):一氧化氮
(NO)cGMP/cGMP依赖的蛋白激酶(G-K)信号转导
通路对于许多生理和生理功能的调节是重要的。
病理生理过程,例如,在心血管系统中
平滑肌细胞、内皮细胞和血小板的主要决定因素
功能,并与高血压的发生和发展有关
动脉硬化。然而,与cAMP依赖的蛋白激酶相比,
已知G-激酶激活的下游效应。这个
研究人员发现,G-激酶调节基因表达:作为对
NO或cGMP,激酶转位到细胞核,诱导磷酸化
表达CREB相关蛋白并激活FOS、JunB和TNF-α
推动者。初步数据表明,G-激酶反式激活这些
转录识别的类似顺式作用元件的启动子
AP-1(Fos-jun)、Cre-和CCAAT-增强子结合蛋白的影响因素
家族及其亚细胞定位和生物活性
激酶受特定锚定蛋白的调节。的特殊目标
这一建议是:(1)确定NO/cGMP反应元件的DNA序列
(NGREs):(Ii)确定靶向转录因子
NO/cGMP/G-激酶;和(Iii)鉴定关键底物和细胞质或
与G-激酶结合的核锚定蛋白。NGRE将由以下内容定义
基因中可能的增强子元件的缺失和定点突变
FOS和肿瘤坏死因子-α启动子。NO/cGMP靶向的转录因子将
在使用Ga14融合产物的反式激活研究中被鉴定
候选转录因子的显性负突变体以及
DNA结合研究和DNA亲和层析
编码NGRE的寡聚脱氧核苷酸。蛋白质相互作用克隆将是
用于鉴定与G-激酶相互作用的蛋白质及其作用
这些蛋白对G-激酶的亚细胞定位和功能的影响
测试过。一氧化氮作为一种信号分子的广泛重要性一直是
最近获得认可;这项拨款申请中建议的研究应
为NO和cGMP的作用机制提供新的见解
哺乳动物细胞。由于NO/cGMP信号的药理学操作
转导途径为多种肿瘤提供了治疗潜力
人类疾病,更好地了解其长期的下游影响
迫切需要NO和cGMP。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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- 批准号:
10588164 - 财政年份:2016
- 资助金额:
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