Trials for development of novel inhibitors for intracellular signaling.
开发新型细胞内信号传导抑制剂的试验。
基本信息
- 批准号:06558095
- 负责人:
- 金额:$ 6.27万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Developmental Scientific Research (B)
- 财政年份:1994
- 资助国家:日本
- 起止时间:1994 至 1995
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
PLC-gamma possesses a phospholipase C inhibitor (PCI) region adjacent to its SH2 and SH3 motifs that strongly suppresses the PIP_2 hydrolyzing activity of purified PLC isoforms in vitro. Synthetic peptides identical to the amino acid sequence of the PCI region (PCI peptides) inhibit PIP_2 hydrolysis induced by each PLC isoforms. It has been demonstrated that the acylation of various synthetic peptides enhances their permeability to the plasma membrane, rendering the peptides potentially specific effectors or inhibitors inside intact cells. Based on this information, we synthesized various kinds of acylated PCI peptides, and examined their effects on intracellular PLC activity using normal fibroblasts and cancer cells. In this study, we obtained following results. 1) We synthe sized 50 kinds of acylated PCI peptides, among which 35 acylated peptides were used in this study. 2) Acylation of the PCI peptides did not alter their specific secondary structure which is conserved among all PCI peptides and probably required for PLC inhibition, and strongly enhanced their PLC inhibitory potency. Acylation of the peptides significantly enhanced their permeability to the plasma membrane, and preincubation of cells with acylated peptides resulted in inhibition of intracellular PLC activation. The inhibitory effects of the peptides varied among types of acylation.4) N-myristoylated PCI peptides, one of the most potent PCI peptides, suppressed the ligand-dependent IP_3 formation in 3Y1 cells (ED_<50>=1muM) and growth of some carcinoma cells. 5) This study indicated a possibility to produce more potent PCI peptides by combination of various N- and C-terminal modifications and a difficulty to produce synthetic compounds structurally related to PCI peptides.
PLC-γ在其SH 2和SH 3基序附近具有磷脂酶C抑制剂(PCI)区域,该区域强烈抑制纯化的PLC异构体的PIP_2水解活性。与PCI区的氨基酸序列相同的合成肽(PCI肽)抑制由每种PLC同种型诱导的PIP_2水解。已经证明,各种合成肽的酰化增强了它们对质膜的渗透性,使得肽在完整细胞内成为潜在的特异性效应物或抑制剂。基于这些信息,我们合成了各种酰化PCI肽,并使用正常成纤维细胞和癌细胞检测了它们对细胞内PLC活性的影响。在这项研究中,我们得到了以下结果。1)我们合成了50种酰化PCI肽,其中35种用于本研究。2)PCI肽的酰化没有改变它们的特异性二级结构,这在所有PCI肽中是保守的,并且可能是PLC抑制所需的,并且强烈增强了它们的PLC抑制效力。酰化的肽显着增强其渗透性的质膜,和预孵育的细胞与酰化的肽导致细胞内PLC激活的抑制。4)N-肉豆蔻酰化的PCI肽抑制3 Y1细胞IP_3的形成(艾德_<50>= 1 μ M)和某些癌细胞的生长,是最有效的PCI肽之一。5)该研究表明通过各种N-和C-末端修饰的组合产生更有效的PCI肽的可能性,以及产生结构上与PCI肽相关的合成化合物的困难。
项目成果
期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
M.K.Homma et.al.: "Enhanced phosphoinositide metabolism in colorecta carcinoma cells derived from familial adenomatous polyposis patients." J.Cell.Biochem.55. 477-485 (1994)
M.K.Homma 等人:“来自家族性腺瘤性息肉病患者的结直肠癌细胞中磷酸肌醇代谢增强。”
- DOI:
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- 影响因子:0
- 作者:
- 通讯作者:
本間 好: "ホスホリパーゼC" 実験医学. 14. 192-194 (1996)
Yoshi Honma:“磷脂酶 C”实验医学。14. 192-194 (1996)
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
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Tsutsumi,T.et al.: "A Iysophosphoinositide-specific phospholipase C distinct from other phospholipase C families in rat brain." Arch.Biochem.Biophys.317. 331-336 (1995)
Tsutsumi,T.et al.:“一种与大鼠脑中其他磷脂酶 C 家族不同的溶血磷酸肌醇特异性磷脂酶 C。”
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
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- 通讯作者:
Homma,Y.& Emori,Y.: "A dual signal mediator showing RhoGAP and phospholipase C-δ stimulating activities." EMBO J.14. 286-291 (1995)
Homma, Y. 和 Emori, Y.:“显示 RhoGAP 和磷脂酶 C-δ 刺激活性的双重信号介质。” EMBO J.14 (1995)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
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- 通讯作者:
Iiri,T.et al.: "Potentiation of Gi-mediated PLC activation by retinoic acid in HL-60 cells: Possible role of G(g2)." J.Biol.Chem.270. 5901-5908 (1995)
Iiri,T.et al.:“视黄酸在 HL-60 细胞中增强 Gi 介导的 PLC 激活:G(g2) 的可能作用。”
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- 影响因子:0
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HOMMA Yoshimi其他文献
HOMMA Yoshimi的其他文献
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{{ truncateString('HOMMA Yoshimi', 18)}}的其他基金
Studies on molecular basis for regulation of beta-oxidation system
β-氧化系统调控的分子基础研究
- 批准号:
21590314 - 财政年份:2009
- 资助金额:
$ 6.27万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of DNA methylation pattern of promoter CpG islands in idiopathic pulmonary fibrosis.
特发性肺纤维化启动子CpG岛DNA甲基化模式分析
- 批准号:
15390257 - 财政年份:2003
- 资助金额:
$ 6.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Cooperative study on molecular mechanism of GFAP expression.
GFAP表达分子机制合作研究。
- 批准号:
10044307 - 财政年份:1998
- 资助金额:
$ 6.27万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Studies on ontogenic significance of PLC signaling systems.
PLC信号系统的本体意义研究。
- 批准号:
10480172 - 财政年份:1998
- 资助金额:
$ 6.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Identification and functional analysis of proteins involved in novel pathway for PLC activation.
PLC 激活新途径中涉及的蛋白质的鉴定和功能分析。
- 批准号:
08458184 - 财政年份:1996
- 资助金额:
$ 6.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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PIP 磷酸酶和肌醇磷脂稳态
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6240981 - 财政年份:1996
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肌醇磷脂包裹的第二信使的调节
- 批准号:
07044216 - 财政年份:1995
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$ 6.27万 - 项目类别:
Grant-in-Aid for international Scientific Research
Role of tyrosine Kinase in platelet inositol phospholipid metabolism
酪氨酸激酶在血小板肌醇磷脂代谢中的作用
- 批准号:
03671182 - 财政年份:1991
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"Study on physical properties of inositol phospholipid in cellular signal transduction"
《肌醇磷脂在细胞信号转导中的物理性质研究》
- 批准号:
01580262 - 财政年份:1989
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Inositol phospholipid metabolism in cerebral ischemia
脑缺血时肌醇磷脂代谢
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62480303 - 财政年份:1987
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Grant-in-Aid for General Scientific Research (B)
Mechanism and role of inositol phospholipid turnover in yeast morphogenesis
肌醇磷脂周转在酵母形态发生中的机制和作用
- 批准号:
60560090 - 财政年份:1985
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Grant-in-Aid for General Scientific Research (C)
ROLE OF G-PROTEINS IN THE CONTROL OF INOSITOL PHOSPHOLIPID HYDROLYSIS IN T-CELLS
G 蛋白在控制 T 细胞中肌醇磷脂水解中的作用
- 批准号:
3811105 - 财政年份:
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PIP PHOSPHATASE AND INOSITOL PHOSPHOLIPID HOMEOSTATSIS
PIP 磷酸酶和肌醇磷脂稳态
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5212607 - 财政年份:
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$ 6.27万 - 项目类别: