Regulation of natural antibody binding and susceptibility to natural killer cells through Zn(++)-inducible ras oncogene expression.
Changes in the natural resistance phenotype were examined for the 2H1, 10T 1/2 cells expressing the activated human H-ras oncogene under the transcriptional regulation of the zinc-inducible mouse metallothionein-I promoter. Culture of the cells in 50 microM ZnSO4 induced an increase in ras protein p21 levels which were maximal within 1 day. Natural-antibody (NAb) binding was significantly increased following 2 days of cell culture in ZnSO4 and continued to increase up to 4 days. The increased NAb binding returned to uninduced levels within 2 days following the removal of added zinc ions from the culture medium. The cells also exhibited a significant increase in natural killer (NK) cell sensitivity following 2 days in ZnSO4. This was maintained as long as the zinc was in the medium, but returned to uninduced levels within 1 day following its removal. The results show that NAb binding and susceptibility to NK cells increased following ras oncogene expression in 10T 1/2 cells and that both parameters were regulated by p21 expression. Repeated i.v. administration of whole-serum NAb prior to tumor inoculation reduced the number of early tumors following s.c. injection of Zn(++)-induced 2Hl cells into Zn(++)-treated C3H/HeN mice, consistent with an in vivo role for NAb in the defense against ras-transformed cells. In contrast, small but statistically significant reductions in NAb binding were observed following v-H-ras transformation of NIH 3T3 cells or v-src transformation of 10T 1/2. The data argue for an NAb- and NK-cell-susceptible phase of ras-induced tumor development which is a prerequisite for these mediators to contribute to a first line of defense against incipient neoplasia, and suggest that characteristics of the recipient cell and the transforming oncogene are important in determining the natural resistance phenotype.
Tough
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DF
Department of Immunology, University of Manitoba, Winnipeg, Canada.
Haliotis
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T
Chow
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DA
D016475:3T3 Cells; D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D015870:Gene Expression / Q000187:drug effects; D011905:Genes, ras; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology
D000912:Antibodies, Neoplasm; D008668:Metallothionein; D016283:Proto-Oncogene Proteins p21(ras); D015032:Zinc