Interferon regulatory factor 1 promoter polymorphism and response to type 1 interferon.
The clinical success of interferon-treatment has been found to vary in different individuals. To explain this, we hypothesized that responses to type 1 interferons could be partly determined by interferon regulatory factor-1 gene transcription, because the latter is an important transcription factor in the interferon system. We demonstrated that the antiproliferative effect of type 1 interferons on human liver cancer cells correlates with levels of transcription of the interferon regulatory factor-1 gene in parallel with those of p21(WAF-1) expression. Here, we investigated whether mutations in the interferon regulatory factor-1 gene cause different responses to type 1 interferons. DNA from several human liver cancer cell lines and peripheral blood mononuclear cells was investigated. Nucleotide sequences of the interferon regulatory factor-1 gene and polymerase chain reaction products of its upstream region were determined directly and after cloning. The promoter activity of the upstream region of this gene was measured by the luciferase reporter assay. We found 4 point mutations in the upstream (- 1 approximately - 495) region, and the luciferase promoter assay demonstrated that these mutations did modify promoter activity. Analysis of DNA from healthy volunteers showed that these mutations are single nucleotide polymorphisms. These results suggest that single nucleotide polymorphisms of the interferon regulatory factor-1 promoter contribute, at least in part, to determining responses to type 1 interferons. J. Cell. Biochem. Suppl. 36: 191-200, 2001.
Saito
H
H
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. hsaito@med.keio.ac.jp
Tada
S
S
Ebinuma
H
H
Wakabayashi
K
K
Takagi
T
T
Saito
Y
Y
Nakamoto
N
N
Kurita
S
S
Ishii
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I / Q000494:pharmacology*; D007438:Introns; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D010750:Phosphoproteins; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases