Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer.
Loss of heterozygosity (LOH) observed in human tumors strongly suggests the existence of (a) tumor-suppressor gene(s) at the concerned locus. A series of studies has revealed that LOH on the long arm of chromosome 5 (5q) frequently occurs in differentiated gastric adenocarcinomas. Furthermore, it has been shown that the interferon regulatory factor-1 (IRF-1) locus on chromosome 5q31.1 is one of the common minimal regions of LOH in these cancers. IRF-1 is a transcriptional activator that shows tumor-suppressor activity in the mouse. In the present study, we examined the sequence of the IRF-1 gene in 9 cases of histologically differentiated gastric adenocarcinomas, all of which exhibited LOH at the IRF-1 locus. We identified a mis-sense mutation in the residual allele in one case. This mutated form of IRF-1 showed markedly reduced transcriptional activity. In addition, overexpression of wild-type IRF-1 induced cell-cycle arrest, whereas such activity was attenuated in the mutant IRF-1. These results suggest that the loss of functional IRF-1 is critical for the development of human gastric cancers.
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Japan.
H
H
Nozawa
E
E
Oda
S
S
Ueda
G
G
Tamura
C
C
Maesawa
T
T
Muto
T
T
Taniguchi
N
N
Tanaka
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D019656:Loss of Heterozygosity; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D017354:Point Mutation; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins