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Basic analysis for development of inhibitors of malignant glioma invasion

恶性胶质瘤侵袭抑制剂研发的基础分析

基本信息

批准号：
12557119
负责人：
SAYA Hideyuki
金额：
$ 8.38万
依托单位：
Kumamoto University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557119/
关键词：
adhesion molecule CD44 metalloprotease transcription γ-secretase cadherin hyaluronic acid invasion 細胞運動 Ras Rho Rac

项目摘要

Cell surface adhesion molecules are crucial for the migratory process, as they couple interactions with the extracellular matrix (ECM) to the cytoskeletal apparatus inside the cell. CD44 is the principal cell adhesion receptor for several extracellular matrix components, mainly hyaluronic acid which is abundant in brain tissue. We found that CD44 expressed in cancer cells is proteolytically cleaved at the ectodomain through membrane-anchored metalloproteases under various physiological conditions including calcium influx, activation of PKC and activation of Ras proto-oncogene product. We found that this cleavage is responsible for dynamic regulation of the interaction between CD44 and the extracellular matrix and plays a critical role in cancer cell migration. In the present study, we found that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (CD44ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate (TPA) responsive element (TRE), which is found in numerous genes involved in diverse cellular processes. We demonstrate that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel signaling pathway that links proteolytic processing of an adhesion molecule at the cell surface to transcriptional activation in the nucleus. Therefore, CD44 can be a novel molecular target for prevention of glioma invasion.

细胞表面的黏附分子对迁移过程至关重要，因为它们与细胞外基质(ECM)和细胞内的细胞骨架装置相互作用。CD44是几种细胞外基质成分的主要细胞黏附受体，主要是脑组织中丰富的透明质酸。我们发现，在各种生理条件下，癌细胞中表达的CD44通过膜锚定的金属蛋白水解酶在胞外区域被切割，包括钙内流、PKC激活和RAS原癌基因产物的激活。我们发现，这种裂解负责动态调节CD44和细胞外基质之间的相互作用，并在癌细胞迁移中发挥关键作用。在本研究中，我们发现CD44在胞外区和胞内区经历了一系列的蛋白降解，导致CD44胞内区(CD44ICD)片段的释放。因此，CD44ICD作为一种信号转导分子，通过12-O-十四酰佛波醇13-乙酸酯(TPA)反应元件(TPA)激活转录，该元件存在于参与多种细胞过程的众多基因中。我们证明CD44ICD增强了转录共激活因子CBP/p300介导的反式激活。此外，我们还发现CD44基因是CD44ICD转录激活的潜在靶点之一。这些观察建立了一条新的信号通路，将细胞表面黏附分子的蛋白水解性处理与细胞核中的转录激活联系起来。因此，CD44可作为预防脑胶质瘤侵袭的新的分子靶点。