Connexins in tumour suppression and cancer therapy.
Connexins in tumour suppression and cancer therapy.
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连接蛋白在肿瘤抑制和癌症治疗中的作用。
DOI：
10.1002/9780470515587.ch15
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发表时间：
1999
影响因子：
--
通讯作者：
Mesnil,M
中科院分区：
文献类型：
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作者：
Yamasaki,H;Omori,Y;Krutovskikh,V;Zhu,W;Mironov,N;Yamakage,K;Mesnil,M
恶性细胞通常表现为细胞间缝隙连接通讯的改变，并且常常与连接蛋白的异常表达或定位有关。将连接蛋白基因导入致瘤细胞可使细胞恢复正常生长，提示连接蛋白形成肿瘤抑制基因家族。一些研究还表明，特定的连接蛋白可能是控制特定细胞类型的生长所必需的。虽然我们已经发现编码Cx32(Cx32；β1)、Cx37(α4)和Cx43(α1)的基因在肿瘤中很少发生突变，但我们最近的研究表明，连接蛋白基因启动子的甲基化可能是连接蛋白基因表达在某些转折中下调的机制。我们已经产生了编码Cx26(β2)、Cx32和Cx43基因的各种显性负突变，其中一些阻碍了相应野生型基因的生长控制。十年前，我们提出了一种通过缝隙连接扩散治疗药物来增强杀灭癌细胞的方法。最近，我们和其他人已经证明，缝隙连接细胞间通讯是单纯疱疹病毒胸苷激酶/更昔洛韦基因治疗中出现的旁观者效应的原因。因此，连接蛋白基因可以在肿瘤控制中发挥双重作用：肿瘤抑制和癌症治疗的旁观者效应。
Malignant cells usually show altered gap junctional intercellular communication and are often associated with aberrant expression or localization of connexins. Transfection of connexin genes into tumorigenic cells restores normal cell growth, suggesting that connexins form a family of tumour suppressor genes. Some studies have also shown that specific connexins may be necessary to control growth of specific cell types. Although we have found that genes encoding connexin32 (Cx32; β1), Cx37 (α4) and Cx43 (α1) are rarely mutated in tumours, our recent studies suggest that methylation of the connexin gene promoter may be a mechanism by which connexin gene expression is down‐regulated in certain turnours. We have produced various dominant negative mutants of the genes encoding Cx26 (β2), Cx32 and Cx43, some of which prevent the growth control exerted by the corresponding wild‐type genes. A decade ago, we proposed a method to enhance killing of cancer cells by diffusion of therapeutic agents through gap junctions. Recently, we and others have shown that gap junctional intercellular communication is responsible for the bystander effect seen in herpes simplex virus thymidine kinase/ganciclovir gene therapy. Thus, connexin genes can exert dual effects in tumour control: tumour suppression and a bystander effect for cancer therapy.