Zhong Xiaoling, Arita Michitsune, Yamada Kanae, Sugiyama Hisahiko, Tan Ke, Kanazawa Shinsaku, Koike Junichi, Teramoto Tatsuo, Hemmi Hiromichi
Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo, 143-8540, Japan.
Biochem Genet. 2007 Oct;45(9-10):671-81. doi: 10.1007/s10528-007-9104-z. Epub 2007 Aug 10.
Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position -107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three -107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The -107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with -107C (P<0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified -107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of -107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including -107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression.
DNA错配修复基因hMLH1的失活使人易患结直肠癌。我们在163例结直肠癌患者中的3例中，鉴定出相对于hMLH1基因翻译起始位点在-107位的C到G核苷酸替换，等位基因频率为0.0092（3/326）。这三个-107G等位基因中的一个出现在肿瘤组织中hMLH1表达降低的五名患者中的一名患者中。在63名健康个体中未发现-107G。与-107C相比，这种替换使转录活性降低了51%（P<0.01），并阻碍了核蛋白与启动子的结合能力。虽然鉴定出的-107G等位基因数量较少，不足以评估其对肿瘤发生和临床病理特征的贡献，但-107G对hMLH1基因转录和核蛋白与启动子序列结合的影响表明，包括-107C在内的该位点是与维持hMLH1基因表达的激活剂相互作用的关键元件。
