Inhibitory effect on natural killer activity of microphthalmia transcription factor encoded by the mutant mi allele of mice.
The mouse mi locus encodes a basic-helix-loop-helix-leucine zipper-type transcription factor, microphthalmia transcription factor (MITF). Mice of mi/mi genotype express a mutant form of MITF (mi-MITF), whereas mice of tg/tg genotype have a transgene in the 5' flanking region of the mi gene and do not express MITF. Although the mi/mi mouse is deficient in natural killer (NK) activity, it was found that the tg/tg mouse was normal in this respect. To know the cause, spleen cells of both genotypes were compared. Although the proportion of spleen cells expressing an NK cell marker, NK1.1, was comparable in both mice, the proportion of large granular lymphocytes decreased only in mi/mi mice. The difference between mi/mi and tg/tg mice was reproducible in the culture supplemented with interleukin-2. Moreover, the perforin gene expression was reduced in mi/mi-cultured spleen cells. Wild-type (+) MITF transactivated, but mi-MITF suppressed, the perforin gene promoter through the NF-P motif, a strong cis-acting element. However, neither +-MITF nor mi-MITF bound the NF-P motif. Instead, 2 nuclear factors that bound the NF-P motif were retained in the cytoplasm of mi/mi-cultured spleen cells. In addition, overexpression of mi-MITF resulted in cytoplasmic retention of the 2 NF-P motif-binding factors in cytotoxic T lymphocytes. The presence of mi-MITF rather than the absence of +-MITF appeared to lead to poor transactivation of the NF-P motif by intercepting NF-P motif-binding factors. This inhibitory effect of mi-MITF may cause the deficient cytotoxicity of NK cells in mi/mi mice. (Blood. 2001;97:2075-2083)
Department of Pathology, Osaka University Medical School, Suita, Osaka, Japan.
A
A
Ito
T R
TR
Kataoka
D K
DK
Kim
Y
Y
Koma
Y M
YM
Lee
Y
Y
Kitamura
D000483:Alleles; D000818:Animals; D000941:Antigens / Q000032:analysis; D000950:Antigens, Ly; D000954:Antigens, Surface; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051739:Microphthalmia-Associated Transcription Factor; D016254:Mutagenesis, Insertional; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009687:Nuclear Proteins / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000032:analysis; D012045:Regulatory Sequences, Nucleic Acid; D013154:Spleen / Q000473:pathology; D014157:Transcription Factors; D015533:Transcriptional Activation; D019076:Transgenes
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D007376:Interleukin-2; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009687:Nuclear Proteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D014157:Transcription Factors; D054353:Perforin; D004247:DNA