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Development of specific prevention against people with high susceptibility for cancer and general carcinogenesis

开发针对癌症高易感人群和一般癌变的特异性预防措施

基本信息

批准号：
10470097
负责人：
SAKAI Toshiyuki
金额：
$ 8.32万
依托单位：
Kyoto Prefectural University 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：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

1. p27 is a crucial tumor-suppressor gene. Vitamin D3 (VD3) activated p27 via promoter region and repressed cell growth. VD3 stimulated transcription of the p27 by a novel mechanism involving Sp1 and NF-Y, but not the VD3 receptor. These results indicate that we could develop a new drug without side effect such as hypercalcemia mediated by the VD3 receptor.2. Butyrate, a dietay fiber metabolite, activated p21/WAF1 and acted as histone deacetylase (HDAC) inhibitor. We previously reported that butyrate activated p21/WAF1 by Sp1 and Sp3 through Sp1 site of the promoter. Moreover, butyrate activated gadd45 causing cell-cycle arrest and DNA repair. This activation is mediated through Oct-1 box and CCAAT box. p21/WAF1 and gadd45 are regulated by p53. p53 is critical factor in Li-Fraumeni syndrome and is inactivated in a half of malignancies. HDAC inhibitors which activate p21/WAF1 and gadd45 mght be preventive against patient of Li-Fraumeni syndrome or common cancer.3. p16 as well as p53 is a gene inactivated in a half of malignancies. The promoter regions of p16 gene, p15-family genes (p15, p18 and p19) and p53-regulated genes (BAX, DR5, Sian-1 and PUMA) were cloned. We screened drugs activating these genes via these promoter regions and found intersting regulators. These regulators may become novel drugs for prevention of specific cancer.

1. P27是一个重要的肿瘤抑制基因。维生素D3 （VD3）通过启动子区激活p27，抑制细胞生长。VD3通过一种涉及Sp1和NF-Y的新机制刺激p27的转录，而不是VD3受体。这些结果表明，我们可以开发出一种无VD3受体介导的高钙血症等副作用的新药。丁酸盐是膳食纤维的代谢物，可激活p21/WAF1，并作为组蛋白去乙酰化酶（HDAC）抑制剂。我们之前报道过丁酸盐通过Sp1和Sp3激活p21/WAF1启动子的Sp1位点。此外，丁酸盐激活gadd45导致细胞周期阻滞和DNA修复。这种激活是通过Oct-1盒子和CCAAT盒子介导的。p21/WAF1和gadd45受p53调控。p53是Li-Fraumeni综合征的关键因子，在一半的恶性肿瘤中失活。激活p21/WAF1和gadd45的HDAC抑制剂可能对Li-Fraumeni综合征或普通癌症患者有预防作用。P16和p53在一半的恶性肿瘤中都是失活的基因。克隆了p16基因启动子区、p15家族基因（p15、p18和p19）和p53调控基因（BAX、DR5、Sian-1和PUMA）。我们筛选了通过这些启动子区域激活这些基因的药物，并发现了有趣的调节因子。这些调节剂可能成为预防特定癌症的新药。