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Application of a new tumor cell motility stimulating factor, PD-I family proteins todiagnosis and treatment of cancer.

新型肿瘤细胞运动刺激因子PD-1家族蛋白在癌症诊断和治疗中的应用。

基本信息

批准号：
08670177
负责人：
SANO Kimihiko
金额：
$ 1.41万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

I have cloned two new members belonging to a phosphodiesterase I gene fimily from rat, and designated as PD-Ialpha and-beta. In current study I have cloned human PD-Ialpha and -beta and peroformed further analysis. I have found that human PD-Ialpha is an alternative splicing product of autotaxin, which is a newly found autocrine tumor cell motility-stimulating factor. I examined the expression of human PD-Ialpha/ATX gene in human neuroblastoma tumor tissues, motility stimulating activity of recombinant ATX on neuroblastoma cells, and investigated its transcriptional regulatory mechanism in a human neuroblastoma cell line. PD-Ialpha/ATX gene was expressed in the primary tumor tissues from the neuroblastoma patients at a various extent. This gene is also expressed in a SMS-KAN neuroblastoma cell line. We indentified both isoforms, PD-Ialpha and ATX,in these tumor tissues and SMS-KAN cells. The recombinant ATX stimulated the motility of SMS-KAN cells at low nanomolar concentration. We situated the promoter region, which is essential for its transcription in SMS-KAN cells, at-287 nt to -254 nt by the promoter activity assay. The gel shift assay revealed that there exists a nuclear protein in SMS-KAN cells that binds this region. These new insights about autocrine tumor cell motility-stimulating protein will help us to understand the metastatic mechanism of human neuroblastoma.I have also cloned human PD-Ibeta. PD-Ibeta gene expression was mostly observed in the prostate and uterus. I have also shown that PD-Ialpha and beta are localized to human chromosome 8q24.1 and 6q22, respectively.

本研究从大鼠中克隆了属于磷酸二酯酶I基因家族的两个新成员，分别命名为PD-Ⅰ α和PD-Ⅰ β。在本研究中，我克隆了人PD-1 α和β，并进行了进一步的分析。我发现人PD-I α是自分泌运动因子autotaxin的选择性剪接产物，autotaxin是一种新发现的自分泌肿瘤细胞运动刺激因子。我检测了人PD-1 α/ATX基因在人神经母细胞瘤肿瘤组织中的表达，重组ATX对神经母细胞瘤细胞的运动刺激活性，并研究了其在人神经母细胞瘤细胞系中的转录调控机制。PD-I α/ATX基因在神经母细胞瘤患者的原发肿瘤组织中有不同程度的表达。该基因也在SMS-KAN神经母细胞瘤细胞系中表达。我们在这些肿瘤组织和SMS-KAN细胞中鉴定了PD-I α和ATX两种亚型。重组ATX在低纳摩尔浓度下刺激SMS-KAN细胞的运动。通过启动子活性测定，我们将其在SMS-KAN细胞中转录所必需的启动子区域定位在-287 nt至-254 nt。凝胶迁移实验表明，在SMS-KAN细胞中存在与该区域结合的核蛋白。这些关于自分泌肿瘤细胞运动刺激蛋白的新认识将有助于我们了解人神经母细胞瘤的转移机制。PD-I β基因表达主要见于前列腺和子宫。我还表明，PD-1 α和β分别定位于人类染色体8q24.1和6 q22。