Point mutations and deletions in the znfn1a1/ikaros gene in chemically induced murine lymphomas.
The Znfn1a1 gene encodes a zinc finger protein called Ikaros, which is criticalfor T-cell development and differentiation. The execution of normal function of Ikaros requires sequence-specific DNA binding, transactivation, and dimerization domains. In this study, exons 3-5 and exon 7 of the Znfn1a1 gene that encode the functional domains of Ikaros were analyzed for point mutations and deletions in murine lymphomas induced by 1,3-butadiene, 2',3'-dideoxycytidine, or phenolphthalein. Missense and frameshift mutations were identified in 11% (11 of 104) of the tumors. Interestingly, 8 of the mutations were identified in the NH2-terminal zinc finger motifs, which are crucial for the DNA-binding function of Ikaros. The other 3 samples carried frameshift mutations in exon 7 that resulted in truncations and abrogation of both transactivation and dimerization domains. One tumor with a missense mutation in the DNA-binding domain also displayed a 45-bp deletion in the dimerization domain. Southern analysis disclosed interstitial homozygous deletions in the functional domains of Ikaros in 4% (3 of 68) of the lymphomas examined. Allelic losses on markers surrounding the Znfn1a1 gene were detected in 27% (12 of 45) of the tumors analyzed. However, only 2 tumors with allelic losses also showed mutations in the Znfn1a1 gene, indicating that other tumor suppressor genes located on this region might be involved as well. Our results suggest inactivation of Ikaros in a subset of chemically induced lymphomas and additionally support the contention of tumor-suppressor activity for Ikaros.
Karlsson
Anneli
A
Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden.
Söderkvist
Peter
P
Zhuang
Shi-Mei
SM
D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D002070:Butadienes; D002273:Carcinogens; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D020868:Gene Silencing; D051740:Ikaros Transcription Factor; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020113:Phenolphthalein; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics*; D016047:Zalcitabine
D002070:Butadienes; D002273:Carcinogens; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D016047:Zalcitabine; D020113:Phenolphthalein; C031763:1,3-butadiene