Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells
Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells
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DOI：
10.1016/s0304-3835(02)00592-x
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发表时间：
2003-02-28
期刊：
影响因子：
9.7
通讯作者：
Ohnishi, T
中科院分区：
文献类型：
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作者：
Harada, H;Nakagawa, K;Ohnishi, T
恶性胶质瘤与低级别胶质瘤的区别在于其强烈的血管生成。在神经胶质瘤中，p53是最常改变的基因，并且参与神经胶质瘤发展的早期阶段。与此相反，纯合性p16基因缺失在高级别胶质瘤中更常见。为了了解胶质瘤在恶性转化过程中血管生成增加的机制，我们研究了血小板反应蛋白-1（血管生成的负调节因子）与恶性胶质瘤中这些肿瘤抑制基因之间的关系。用含有野生型p53、p16和p21的cDNA的重组复制缺陷型腺病毒载体转导具有突变的p53和缺失的p16的人神经胶质瘤细胞系U-251 MG。只有野生型p53的诱导增强U-251 MG细胞中血小板反应蛋白-1 mRNA和蛋白的表达。此外，。在用Ad 5CMV-p53感染后36小时，与病毒对照相比，在培养基中分泌的血小板反应蛋白-1显著增加（3.8倍）。在野生型p53质粒DNA的存在下，与空表达载体对照相比，启动子活性增加了7.4倍。这些研究可能表明，p53基因突变赋予胶质瘤血管生成表型通过减少血小板反应蛋白-1的生产，以及增强血管生成诱导剂在恶性进展的早期阶段。(C)2002爱思唯尔科学爱尔兰有限公司保留所有权利。
Malignant gliomas are distinguished from low-grade gliomas by their intense angiogenesis. In gliomas, p53 is the most frequently altered gene and is involved in the early phase of glioma development. In contrast, homozygous p16 gene deletion is more common in high-grade gliomas. In order to understand the mechanism by which gliomas become more angiogenic during the malignant transformation, we examined the relationship between thrombospondin-1, a negative regulator in angiogenesis, and these tumor suppressor genes in malignant gliomas. Human glioma cell line U-251 MG, which has mutated p53 and deleted p16, was transduced with recombinant replication-defective adenovirus vectors containing the cDNA of wild-type p53, p16, and p21. Only the induction of wild-type p53 enhanced expression of thrombospondin-1 mRNA and the protein in U-251 MG cells. Furthermore,. thrombospondin-1 that was secreted in the culture medium was significantly increased (3.8-fold) as compared with that of the viral control 36 h after infection with Ad5CMV-p53. In the presence of wild-type p53 plasmid DNA, the promoter activity was increased 7.4-fold as compared with an empty expression vector control. These studies may suggest that mutation of p53 gene endows gliomas with an angiogenic phenotype by reducing thrombospondin-1 production as well as enhancing the angiogenesis inducers in the early phase of malignant progression. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.