title: A single nucleotide substitution (-107C-->G) in the hMLH1 promoter found in colorectal cancer population reduces transcriptional activity.
abstract: 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.
authors: Department of Molecular Biology, Faculty of Medicine, Toho University, 5-21-16 Ohmori-Nishi, Ohta-Ku, Tokyo, 143-8540, Japan.
authors: Xiaoling
authors: X
authors: Zhong
authors: Michitsune
authors: M
authors: Arita
authors: Kanae
authors: K
authors: Yamada
authors: Hisahiko
authors: H
authors: Sugiyama
authors: Ke
authors: K
authors: Tan
authors: Shinsaku
authors: S
authors: Kanazawa
authors: Junichi
authors: J
authors: Koike
authors: Tatsuo
authors: T
authors: Teramoto
authors: Hiromichi
authors: H
authors: Hemmi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1