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Regulation of natural antibody binding and susceptibility to natural killer cells through Zn ++ ‐inducible ras oncogene expression
Author(s) -
Tough David F.,
Haliotis Tina,
Chow Donna A.
Publication year - 1992
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910500317
Subject(s) - oncogene , metallothionein , biology , microbiology and biotechnology , cell culture , antibody , natural killer cell , cell , in vitro , immunology , cell cycle , cytotoxicity , biochemistry , gene , genetics
Changes in the natural resistance phenotype were examined for the 2H1, 10T½ cells expressing the activated human H‐ ros oncogene under the transcriptional regulation of the zinc‐ inducible mouse metallothionein‐1 promoter. Culture of the cells in 50 μM ZnSO 4 induced an increase in ras protein p21 levels which were maximal within I day. Natural‐antibody (NAb) binding was significantly increased following 2 days of cell culture in ZnSO 4 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 ZnSO 4 . This was maintained as long as the zinc was in the medium, but returned to uninduced levels within I day following its removal. The results show that NAb binding and susceptibility to NK cells increased following ras oncogene expression in 10T½ 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 2HI 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 10T½. 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.