期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：13
页码：7824-7829
DOI：10.1073/pnas.1332160100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：PKC-interacting protein (PKCI), also designated histidine triad nucleotide-binding protein 1, belongs to the histidine triad (HIT) family of proteins. Its structure is highly conserved from bacteria to humans and shares homology with the tumor-suppressor gene fragile histidine triad (FHIT). Although it was originally thought to inhibit PKC, its actual physiologic function is not known. Therefore, we used the technique of homologous recombination to generate homozygous deleted PKCI-/- mice. These mice display normal fetal and adult development. However, when mouse embryo fibroblasts were established from 13.5-day embryos and serially passaged the PKCI-/- cells displayed an increase in growth rate and underwent spontaneous immortalization, whereas the PKCI+/+ cells senesced and ceased growing. Furthermore, the PKCI-/- mouse embryo fibroblasts displayed increased resistance to cytotoxicity by ionizing radiation. In view of these findings we examined possible effects of PKCI on susceptibility to carcinogenicity. Both PKCI+/+ and PKCI-/- mice were treated with the chemical carcinogen N-nitrosomethylbenzylamine (NMBA) by intragastric administration and killed 12 weeks later. As expected with this protocol, NMBA induced squamous tumors (both papillomas and carcinomas) of the forestomach. The incidence, multiplicity per mouse, volume, and degree of malignancy of these tumors were significantly greater in the PKCI-/- than in the PKCI+/+ mice. Furthermore, four adenomas and one adenocarcinoma of the glandular stomach were found in the NMBA-treated PKCI-/- mice but no tumors of the glandular stomach were found in the NMBA-treated PKCI+/+ mice or in any of the untreated mice. Taken together, these findings suggest that, like FHIT, PKCI may normally play a tumor-suppressor role. The possible role of PKCI as a tumor suppressor in humans remains to be determined.
