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腫瘍増殖と薬剤耐性を標的とした癌の遺伝子治療

针对肿瘤生长和耐药性的癌症基因治疗

基本信息

批准号：
10044331
负责人：
KOHNO Kimitoshi
金额：
$ 3.01万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10044331/
关键词：
MDR1 CCAAT YB-1 p53 NF-Y c-Myc HMG1 CTF NF1 c-myc PCNA

项目摘要

From a point of view of drug resistance, we focused on the MDR1 gene expression and, investigated its regulatory mechanism. Promoter region in MDR1 gene has a CCAAT motif, and YB-1 and NF-Y can bind to this motif. The trial of identification of the interacting molecules bound to YB-1 and NF-Y were carried out in Japan and Sweden, respectively. So far, we found that p53 (tumor suppresser gene) interacted YB-1. Then the interaction domain between p53 and YB-1, and the mechanism of MDR1 gene expression by p53 through interaction with YB-1 were investigated in Japan. In Sweden, Prof. Funa identified the c-Myc as a factor which interacted with NF-Y, and investigated the interaction domain of each protein and the effect of mutual interaction on transcriptional regulation of down-stream genes. She also found that p53 binds to NF-Y. She is going to investigate the interaction domain. On the other hand, expression mechanism of the HMG1 and STAT3 genes as genes induced by DNA damage were identified in Japan. It was suggested that HMG1 gene expression was regulated by a transcription factor CTF/NF1 through the binding to the promoter region of HMG1. Furthermore, HMG1 interacted p53, and recognized the cisplatin-damaged DNA, and this recognition activity was enhanced by p53. We also found that STAT3 gene expression was upregulated in cisplatin-resistant cells through alternation of chromatin structure. Prof. Funa and I are going to identify the promising molecules for gene therapy, such as damaged DNA recognition protein, cell-cycle. regulatory protein and DNA repair protein and to construct the molecular interaction map for controlling cancer cell growth.

本研究从耐药的角度出发，重点研究了MDR 1基因的表达及其调控机制。MDR 1基因启动子区有一个CCAAT基序，YB-1和NF-Y可与该基序结合。分别在日本和瑞典进行了与YB-1和NF-Y相互作用分子的鉴定试验。到目前为止，我们发现抑癌基因p53与YB-1相互作用。随后在日本研究了p53与YB-1相互作用的结构域，以及p53通过与YB-1相互作用表达MDR-1基因的机制。在瑞典，Funa教授将c-Myc鉴定为与NF-Y相互作用的因子，并研究了每种蛋白质的相互作用结构域以及相互作用对下游基因转录调控的影响。她还发现p53与NF-Y结合。她将研究交互作用域。另一方面，作为DNA损伤诱导基因的HMG 1和STAT 3基因的表达机制在日本得到了鉴定。提示转录因子CTF/NF 1通过与HMG 1启动子区结合调控HMG 1基因的表达。此外，HMG 1与p53相互作用，识别顺铂损伤的DNA，并且这种识别活性被p53增强。我们还发现，STAT 3基因表达上调顺铂耐药细胞通过改变染色质结构。Funa教授和我将鉴定有希望的基因治疗分子，如受损DNA识别蛋白，细胞周期。调控蛋白和DNA修复蛋白的相互作用，构建调控癌细胞生长的分子相互作用图谱。