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Elucidation of the in vivo function of the Ras/Rap effector phospholipase Cε

阐明 Ras/Rap 效应磷脂酶 Cε 的体内功能

基本信息

批准号：
17390078
负责人：
KATAOKA Tohru
金额：
$ 9.34万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390078/
关键词：
phospholipase C small G protein Ras protein inositol phospholipid signaling inflammation cancer promotion knockout mice transgenic mice 心臓半月弁膜症トランスジェニックマウス

项目摘要

(1) The skin of phospholipase Cε (PLCε) knockout mice exhibited great reduction in inflammatory responses accompanied by edema and in leukocyte infiltration induced by phorbor ester (TPA) treatment compared to that of wild-type mice. Concomitantly, reduced expression of proinflammatory cytokines such as interleukin-1α was observed in keratinocytes and dermal fibroblasts cultured from PLCε knockout mice upon TPA treatment. We also showed that PLCε is activated downstream of TPA, which is mediated by Rap1 activation via RasGRP3, a direct target of TPA. Furthermore, by employing various inflammation-inducing mouse model systems, such as an ulcerative colitis model using dextran sulfate, a contact dermatitis model using dinitrofluorobenzene as a hapten, and an ultraviolet radiation-induced dermatitis, we observed severe decrease in inflammatory responses. These results imply that PLCε plays a crucial and general role in inflammatory responses through induction of proinflammatory cytokines. … More (2) Great reduction in de novo intestinal tumor formation and subsequent malignant progression of Min mice, which carry a loss-of-function mutation in the anti-oncogene APC, was observed on the PLCε-knockout background compared to wild-type background. Taken together with our previous result showing that PLCε knockout mice are highly resistant to tumor formation and subsequent malignant progression in the two stage skin chemical carcinogenesis model, these results are quite interesting because they suggest a close link between inflammation and cancer promotion.(3) We generated PLCε transgenic mice, which overexpress PLCε specifically in skin keratinocytes, by using the Cre-loxP recombination system. Interestingly, these mice exhibited strong skin inflammation accompanied by prominent hyperkeratosis and elevated angiogenesis. The results described in 1-3 suggest that PLCε may make a good molecular target for the development of cancer-preventing drugs or anti-inflammatory drugs.(4) We analyzed molecular mechanisms whereby PLCε knockout mice exhibit defective semilunar valvulogenesis during embryonic period. We showed that PLCε is regulated by downstream signaling from heparin-binding epidermal growth factor-like growth factor (HB-EGF) receptor and inhibits proliferation of valvular precursor cells through inhibition of Smad1/5/8 phosphorylation induced by the bone morphogenetic protein (BMP) receptor stimulation. Less

(1)与野生型小鼠相比，磷脂酶Cε（PLCε）基因敲除小鼠的皮肤表现出显著减少伴有水肿的炎症反应和由佛波酯（TPA）治疗诱导的白细胞浸润。同时，TPA治疗后，在PLCε敲除小鼠培养的角质形成细胞和真皮成纤维细胞中观察到促炎细胞因子（如白细胞介素-1 α）表达减少。我们还发现PLCε在TPA下游被激活，这是由Rap 1通过TPA的直接靶点RasGRP 3激活介导的。此外，通过采用各种炎症诱导小鼠模型系统，例如使用硫酸葡聚糖的溃疡性结肠炎模型、使用二硝基氟苯作为半抗原的接触性皮炎模型以及紫外线辐射诱导的皮炎，我们观察到炎症反应严重减少。这些结果表明，PLCε通过诱导促炎细胞因子在炎症反应中起着关键和普遍的作用。 ...更多信息 (2)与野生型背景相比，在PLCε-敲除背景下观察到Min小鼠的从头肠道肿瘤形成和随后的恶性进展大大减少，Min小鼠携带抗癌基因APC的功能丧失突变。结合我们先前的结果，表明PLCε敲除小鼠在两阶段皮肤化学致癌模型中对肿瘤形成和随后的恶性进展具有高度抗性，这些结果非常有趣，因为它们表明炎症和癌症促进之间存在密切联系。(3)我们利用Cre-loxP重组系统构建了PLCε转基因小鼠，使其在皮肤角质形成细胞中特异性过表达PLCε。有趣的是，这些小鼠表现出强烈的皮肤炎症，伴有显著的角化过度和血管生成增加。1-3中描述的结果表明PLCε可能成为开发抗癌药物或抗炎药物的良好分子靶点。(4)我们分析了PLCε基因敲除小鼠胚胎期半月瓣发育缺陷的分子机制。我们发现PLCε受肝素结合表皮生长因子样生长因子（HB-EGF）受体下游信号的调节，并通过抑制骨形态发生蛋白（BMP）受体刺激诱导的Smad 1/5/8磷酸化来抑制瓣膜前体细胞的增殖。少