MECHANISM OF PHORBOL ESTER-INDUCED LIPID METABOLISM
佛波酯诱导的脂质代谢机制
基本信息
- 批准号:3183624
- 负责人:
- 金额:$ 24.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1986
- 资助国家:美国
- 起止时间:1986-04-01 至 1994-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Disordered signal transduction via the protein kinase C pathway has been
implicated in the development of the neoplastic process. The purpose of
this proposal is to define a potential inhibitory pathway for protein
kinase C. The free sphingoid bases have been shown to antagonize
activation of protein kinase C in vitro and in intact cells. However,
evidence has not been presented to suggest that a pathway involving
sphingolipid metabolism to sphingoid bases serves to inactivate protein
kinase C under physiologic conditions. Recent studies from this
laboratory demonstrated that 1,2-diacylglycerols, the endogenous
activators of protein kinase C, stimulated degradation of the
sphingolipid sphingomyelin in GH3 pituitary cells. This event occurred
via a sphingomyelinase (EC 3.1.4.12). Phorbol esters, the tumor-
promoting activators of protein kinase C, failed to stimulate this
event. Further, sphingomyelinase action was sufficient to inactivate
protein kinase C. These studies suggest that 1,2-diacylglycerols may
activate a negative effector pathway for protein kinase C not utilized
by the phorbol esters. The intention of this proposal is to explore
this concept in detail.
Three distinct cell lines will be utilized for these studies; GH3 rat
pituitary cells, 3T3 mouse fibroblasts and HL-60, human leukemia cells.
The effect of 1,2-diacylglycerols and phorbol esters on the synthesis
and degradation of the choline-containing phospholipids,
phosphatidylcholine and sphingomyelin, will be evaluated. The role of
the cAMP and protein kinase C systems in these processes will be
determined. Sphingomyelin degradation via a spingomyelinase will be
related to protein kinase C activation/inactivation. Receptor-mediated
sphingomyelinase activation and the generation of free sphingoid bases
will be assessed for ligands that utilize the phosphoinositide pathway
for signal transduction. Studies will be performed to determine if
differences in the pattern of biologic responses after 1,2-
diacylglycerols and phorbol esters can be ascribed to sphingomyelinase
action. Hopefully, these studies will reveal a physiologically relevant
inhibitory pathway for protein kinase C and explain some of the
differences observed between cellular activation by 1,2-diacylglycerols
and phorbol esters.
蛋白激酶C途径的信号转导紊乱
与肿瘤过程的发展有关。目的
这项提议是为了定义一条潜在的蛋白质抑制途径。
激酶C。游离的狮身人面像碱基已被证明具有拮抗作用。
蛋白激酶C在体外和在完整细胞中的激活。然而,
目前还没有证据表明,一条涉及
鞘磷脂代谢到狮身人面像碱基起到灭活蛋白质的作用
生理条件下的蛋白激酶C。最近的这方面的研究
实验室证明,1,2-二酰甘油,内源性
蛋白激酶C的激活剂,被刺激降解
GH3垂体细胞中的鞘磷脂鞘磷脂。此事件已发生
通过鞘磷脂酶(EC 3.1.4.12)。佛波酯,肿瘤-
促进蛋白激酶C的激活剂,但未能刺激
事件。此外,鞘磷脂酶的作用足以灭活。
蛋白激酶C。这些研究表明,1,2-二酰甘油可能
激活蛋白激酶C未被利用的负效应通路
佛波尔酯。这项提议的目的是探索
对这一概念进行了详细阐述。
三种不同的细胞系将用于这些研究;GH3大鼠
垂体细胞、3T3小鼠成纤维细胞和HL-60人白血病细胞。
1,2-二酰基甘油和佛波酯对合成的影响
和含胆碱的磷脂的降解,
将对磷脂酰胆碱和鞘磷脂进行评估。的作用
这些过程中的cAMP和蛋白激酶C系统将是
下定决心。通过鞘磷脂酶降解鞘磷脂将是
与蛋白激酶C的激活/失活有关。受体介导
鞘磷脂酶激活与游离狮身人面像碱基的产生
将对利用肌醇磷脂途径的配体进行评估
用于信号转导。将进行研究以确定是否
1,2-二氯苯酚引起的生物反应模式的差异
甘油二酯和佛波酯可归因于鞘磷脂酶
行动。希望这些研究能揭示出一种与生理相关的
蛋白激酶C的抑制途径,并解释了一些
1,2-二酰基甘油对细胞激活的差异
和佛波酯。
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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Richard N Kolesnick其他文献
Richard N Kolesnick的其他文献
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