Phospholipase Cε as a potential molecular target for anti-inflammatory therapy and cancer prevention
Phospholipase Cε as a potential molecular target for anti-inflammatory therapy and cancer prevention
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DOI：
10.2492/inflammregen.31.370
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发表时间：
2011
影响因子：
8.1
通讯作者：
H. Edamatsu;N. Takenaka;Lizhi Hu;T. Kataoka
中科院分区：
文献类型：
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作者：
H. Edamatsu;N. Takenaka;Lizhi Hu;T. Kataoka
磷脂酶Ce （PLCe）由PLCE1编码，是由ras原癌基因产物ras及其相关基因Rap1调控的磷酸肌醇特异性PLC。与其他PLC同工异构体一样，PLCe催化磷脂酰肌醇4,5-二磷酸水解生成第二信使，二酰基甘油和肌醇1,4,5-三磷酸。为了了解PLCe的生理功能，我们创建并分析了PLCe灭活或过量产生的转基因小鼠。PLCe敲除（KO）小鼠对由7,12-二甲基苯[a]蒽引发并由12-肉豆蔻酸13-乙酸磷（PMA）促进的两阶段皮肤化学癌变具有抗性，对APC肿瘤抑制基因功能缺失突变引起的肠道肿瘤发生具有抗性。在PLCe KO小鼠中，与野生型小鼠相比，炎症，如单次应用PMA诱导的与肿瘤发生相关的炎症，以及在过敏性接触超敏反应的引发阶段的炎症，也减弱了。相反，表皮中PLCe的过度表达导致皮肤炎症的发展，这在一定程度上与人类牛皮癣具有相同的特征。在本文中，我们总结了显示PLCe在肿瘤发生和炎症中的作用的数据，并讨论了PLCe研究的未来方向，以开发控制炎症和预防癌症进展的治疗方法。
Phospholipase Ce (PLCe), encoded by PLCE1, is the phosphoinositide-specific PLC regulated by the ras proto-oncogene product Ras and its relative Rap1. Like other PLC isoforms, PLCe catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield second messengers, diacylglycerol and inositol 1,4,5-trisphosphate. To understand the physiological function of PLCe, we have created and analyzed genetically-modified mice in which PLCe is inactivated or overproduced. PLCe knockout (KO) mice are resistant to two-stage skin chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and to intestinal tumorigenesis caused by the loss-of-function mutation of the APC tumor suppressor gene. In PLCe KO mice, inflammation, such as that induced by a single application of PMA, that associated with tumorigenesis, and that in the elicitation phase of allergic contact hypersensitivity, is also attenuated as compared to that in wild-type mice. Conversely, overexpression of PLCe in the epidermis results in the development of skin inflammation that partly shares the features with human psoriasis. In this article, we summarize the data showing the role of PLCe in tumorigenesis and inflammation and discuss the future directions of the study of PLCe for the development of therapies to control inflammation and to prevent cancer progression.