Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting protein growth in mice enhances cell growth and carcinogenesis
Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting protein growth in mice enhances cell growth and carcinogenesis
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DOI：
10.1073/pnas.1332160100
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发表时间：
2003-06-24
影响因子：
11.1
通讯作者：
Weinstein, IB
中科院分区：
文献类型：
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作者：
Su, T;Suzui, M;Weinstein, IB
PKC相互作用蛋白（PKCI），也称为组氨酸三联体核苷酸结合蛋白1，属于组氨酸三联体（HIT）蛋白家族。其结构从细菌到人类高度保守，并与肿瘤抑制基因脆性组氨酸三联体（FHIT）具有同源性。虽然它最初被认为是抑制PKC，但其实际的生理功能尚不清楚。因此，我们使用同源重组技术来产生纯合缺失的PKCI-/-小鼠。这些小鼠显示正常的胎儿和成年发育。然而，当从13.5天的胚胎中建立小鼠胚胎成纤维细胞并连续传代时，PKCI-/-细胞显示出生长速率的增加并经历自发永生化，而PKCI+/+细胞衰老并停止生长。此外，PKCI-/-小鼠胚胎成纤维细胞显示出对电离辐射的细胞毒性的抗性增加。鉴于这些发现，我们研究了PKCI对致癌性易感性的可能影响。PKCI+/+和PKCI-/-小鼠均通过灌胃给予化学致癌物N-亚硝基甲基苄胺（NMBA）进行治疗，并在12周后处死。正如该方案所预期的，NMBA诱导了前胃鳞状肿瘤（乳头状瘤和癌）。PKCI-/-小鼠中这些肿瘤的发生率、每只小鼠的多重性、体积和恶性程度显著高于PKCI+/+小鼠。此外，在NMBA处理的PKCI-/-小鼠中发现腺胃的四个腺瘤和一个腺癌，但在NMBA处理的PKCI+/+小鼠或任何未处理的小鼠中未发现腺胃肿瘤。总之，这些发现表明，像FHIT，PKCI可能通常发挥肿瘤抑制作用。PKCI作为人类肿瘤抑制因子的可能作用仍有待确定。
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.