腫瘍増殖と薬剤耐性を標的とした癌の遺伝子治療

从耐药角度出发，重点关注MDR1基因的表达，探讨其调控机制。MDR1基因启动子区有一个CCAAT基序，YB-1和NF-Y可以结合到该基序上。与YB-1和NF-Y结合的相互作用分子鉴定试验分别在日本和瑞典进行。到目前为止，我们发现p53（肿瘤抑制基因）与YB-1相互作用。然后在日本研究了p53与YB-1的相互作用域，以及p53通过与YB-1相互作用表达MDR1基因的机制。在瑞典，Funa教授发现c-Myc是一个与NF-Y相互作用的因子，并研究了每个蛋白的相互作用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。她将研究交互领域。另一方面，在日本鉴定了HMG1和STAT3基因作为DNA损伤诱导基因的表达机制。这表明，转录因子CTF/NF1通过与HMG1的启动子区结合来调控HMG1基因的表达。此外，HMG1与p53相互作用，识别顺铂损伤的DNA， p53增强了这种识别活性。我们还发现，在顺铂耐药细胞中，STAT3基因表达通过染色质结构的改变而上调。Funa教授和我将确定有希望用于基因治疗的分子，如受损的DNA识别蛋白，细胞周期。调控蛋白和DNA修复蛋白，构建控制癌细胞生长的分子相互作用图谱。

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.