Gap junctions contain cell-cell communicating channels that consist of multimeric proteins called connexins and mediate the exchange of low-molecular-weight metabolites and ions between contacting cells. Gap junctional communication has long been hypothesized to play a crucial role in the maintenance of homeostasis, morphogenesis, cell differentiation, and growth control in multicellular organisms. The recent discovery that human genetic disorders are associated with mutations in connexin genes and experimental data on connexin knockout mice have provided direct evidence that gap junctional communication is essential for tissue functions and organ development. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Cell coupling via gap junctions is dependent on the specific pattern of connexin gene expression. This pattern of gene expression is altered during development and in several pathological conditions resulting in changes of cell coupling. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. However, transcriptional control is one of the most important points. In this review, we summarize recent knowledge on transcriptional regulation of connexin genes by describing the structure of connexin genes and transcriptional factors that regulate connexin expression.
Gap junctions are specialized cell-cell junctions that directly link the cytoplasm of neighboring cells. They mediate the direct transfer of metabolites and ions from one cell to another. Discoveries of human genetic disorders due to mutations in gap junction protein (connexin [Cx]) genes and experimental data on connexin knockout mice provide direct evidence that gap junctional intercellular communication is essential for tissue functions and organ development, and that its dysfunction causes diseases. Connexin-related signaling also involves extracellular signaling (hemichannels) and non-channel intracellular signaling. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. In recent years, it has become clear that epigenetic processes are also essentially involved in connexin gene expression. In this review, we summarize recent knowledge on regulation of connexin expression by transcription factors and epigenetic mechanisms including histone modifications, DNA methylation, and microRNA. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions.
To elucidate what changes in the expression of gap junction proteins (connexins) occur at what stages during multistage mouse skin carcinogenesis in vivo, we immunohistochemically and morphometrically analyzed the expression of connexin 26 (Cx26) and connexin 43 (Cx43) in papillomas, well-, moderately- and poorly-differentiated squamous cell carcinomas, as well as in squamous cell carcinomas at invasion sites and those metastasized into lymph nodes in female CD-1 mice as a result of treatment with dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. In papillomas, no clear reduction of the two connexins was observed; however, Cx26 and Cx43 were frequently co-localized in the same gap junction plaques, whereas the two kinds of Cxs were differentially expressed in normal and surrounding non-tumorous epidermis. In squamous cell carcinomas, the expression of both Cx26 and Cx43 significantly decreased compared with surrounding non-tumorous epidermis and papillomas. The Western blot analysis confirmed that both Cx26 and Cx43 proteins were reduced in squamous cell carcinomas compared with papillomas. Furthermore, the expression of Cx26 was reduced as cancer cells became morphologically less differentiated, while that of Cx43 did not change. Squamous cell carcinomas at invasive sites showed clear reduction of Cx26 and Cx43. In squamous cell carcinomas metastasized into lymph nodes, Cx26 was expressed, but few carcinoma cells expressed Cx43. The localization of E-cadherin on the plasma membrane between cancer cells was maintained even at invasive and metastatic sites. Our data suggest that quantitative and qualitative changes in connexin expression are associated with tumor progression, including the loss of differentiation, and invasion and metastasis, during multistage mouse skin carcinogenesis.
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