Omori Y, Duflot-Dancer A, Mesnil M, Yamasaki H
Unit of Multistage Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Toxicol Lett. 1998 Aug;96-97:105-10. doi: 10.1016/s0378-4274(98)00056-3.
Evidence is accumulating that connexin (Cx) genes form a family of tumor-suppressor genes. Our long-standing study revealed that, in almost all tumors, some abnormality in gap junction is observed, including loss or reduction of expression, aberrant localization of gap junction. In this study, we have examined the dominant-negative effects of mutant (prepared by site-directed mutagenesis) Cx43 constructs in C6 glioma cells, and of mutant Cx26 constructs in HeLa cells, on tumorigenicity. The mutant Cx43 A253V (Ala 253 to Val) inhibited the tumor-suppressive function exerted by wild-type Cx43 in C6 cells. Similarly, the mutant Cx26 P87L (Pro 87 to Leu) manifested dominant-negative inhibition of connexin-mediated cell growth control in HeLa cells. These results suggest that mutations of connexin genes can affect the tumor-suppressive function of gap junction and that gap junctional intercellular communication can be regulated by not only non-genotoxic but also genotoxic activities of environmental carcinogens.
越来越多的证据表明，连接蛋白（Cx）基因构成了一个肿瘤抑制基因家族。我们长期的研究表明，在几乎所有肿瘤中，都观察到缝隙连接存在一些异常，包括表达缺失或减少、缝隙连接的异常定位。在本研究中，我们检测了突变型（通过定点诱变制备）Cx43构建体在C6胶质瘤细胞中以及突变型Cx26构建体在HeLa细胞中对致瘤性的显性负效应。突变型Cx43 A253V（丙氨酸253突变为缬氨酸）抑制了野生型Cx43在C6细胞中发挥的肿瘤抑制功能。同样，突变型Cx26 P87L（脯氨酸87突变为亮氨酸）在HeLa细胞中表现出对连接蛋白介导的细胞生长控制的显性负抑制。这些结果表明，连接蛋白基因的突变可影响缝隙连接的肿瘤抑制功能，并且缝隙连接的细胞间通讯不仅可受环境致癌物的非遗传毒性活性调控，还可受其遗传毒性活性调控。
