文章：

Kaiso-p120ctn复合物在癌症中的作用？

A role for Kaiso–p120ctn complexes in cancer?

原文发布日期：2005-11-18

DOI: 10.1038/nrc1752

类型: Review Article

开放获取: 否

要点：

1. Kaiso is a bi-modal transcriptional repressor of the broad-complex, tramtrack and bric-a-brac/poxvirus and zinc finger (BTB/POZ) subfamily of zinc finger proteins (POZ-ZF). It binds two types of DNA sequences that are located within gene-regulatory regions — methylated CpG islands, and sequence-specific sites. A number of direct gene targets have been identified for each type of DNA interaction, and Kaiso recruits co-repressor components in both contexts.
2. Kaiso's relevance to cancer progression has yet to be fully established, but is indicated by several factors. These include the known importance of DNA methylation in the inactivation of tumour-suppressor genes, Kaiso's direct functional links to gene targets of the canonical Wnt–β-catenin signalling pathway, and alterations in Kaiso's intracellular localization in response to normal or pathological microenvironments.
3. Kaiso was first discovered in association with the armadillo protein p120 catenin (p120ctn), which seems to relieve sequence-specific gene repression by dissociating Kaiso from DNA. This is partially analogous to the extensively studied relief of T-cell factor (TCF)/lymphoid enhancer-binding protein (LEF) transcriptional repression by β-catenin in response to canonical Wnt signals. However, in the context of TCF/LEF, relief from transcriptional repression does not involve dissociation from the DNA.
4. Future work needs to address whether p120ctn also modulates the repressive function of Kaiso in the context of methylated DNA and whether, within gene-regulatory regions, a functional relationship exists between the sequence-specific and methylated CpG island-binding sites of Kaiso.
5. The identification of the signalling pathways that direct the nuclear functions of p120ctn and Kaiso is also of interest. In particular, p120ctn's known interactions with the cadherin cell–cell adhesion complex, including its associated kinases and phosphatases, with the Rho-family GTPases and with several cytoskeletal components are discussed.

要点翻译：

1. Kaiso是一种双模态转录抑制因子，属于锌指蛋白BTB/POZ亚家族。它能结合基因调控区内的两类DNA序列——甲基化CpG岛和序列特异性位点。针对每种DNA相互作用类型均已鉴定出多个直接靶基因，且Kaiso在两种情境下均能招募辅抑制因子复合物。
2. Kaiso与癌症进展的相关性尚未完全明确，但以下因素提示其潜在作用：包括DNA甲基化在肿瘤抑制基因失活中的已知重要性、Kaiso与经典Wnt–β-catenin信号通路靶基因的直接功能联系，以及正常或病理微环境下Kaiso细胞内定位的改变。
3. Kaiso最初被发现与犰狳蛋白p120连环蛋白（p120ctn）存在相互作用，p120ctn似乎通过使Kaiso从DNA解离来缓解序列特异性基因抑制。这与β-catenin响应经典Wnt信号解除TCF/LEF转录抑制的经典机制部分类似，但不同之处在于TCF/LEF的转录抑制解除不涉及DNA解离。
4. 未来研究需探讨p120ctn是否也能调控Kaiso在甲基化DNA情境下的抑制功能，以及Kaiso的序列特异性结合位点与甲基化CpG岛结合位点在基因调控区内是否存在功能关联。
5. 此外，解析指导p120ctn和Kaiso核功能信号通路也具有重要意义。特别需要关注的是p120ctn与钙黏蛋白细胞粘附复合物（包括相关激酶/磷酸酶）、Rho家族GTP酶及多种细胞骨架成分的已知相互作用。

英文摘要：

Kaiso belongs to the zinc finger and broad-complex, tramtrack and bric-a-brac/poxvirus and zinc finger (BTB/POZ) protein family that has been implicated in tumorigenesis. Kaiso was first discovered in a complex with the armadillo-domain protein p120ctn and later shown to function as a transcriptional repressor. As p120ctn seems to relieve Kaiso-mediated repression, its altered intracellular localization in some cancer cells might result in aberrant Kaiso nuclear activity. Intriguingly, Kaiso's target genes include both methylated and sequence-specific recognition sites. The latter include genes that are modulated by the canonical Wnt (β-catenin–T-cell factor) signalling pathway. Further interest in Kaiso stems from findings that its cytoplasmic versus nuclear localization is modulated by complex cues from the microenvironment.

摘要翻译： 

Kaiso属于锌指结构和BTB/POZ蛋白家族，该家族与肿瘤发生有关。Kaiso最初被发现与含有armadillo结构域的蛋白p120ctn形成复合物，后来被证实具有转录抑制功能。由于p120ctn能够解除Kaiso介导的抑制作用，其在某些癌细胞中异常的细胞内定位可能导致Kaiso在核内的异常活性。有趣的是，Kaiso的靶基因既包括甲基化的识别位点，也包括序列特异性的识别位点。后者包括受经典Wnt（β-连环蛋白-T细胞因子）信号通路调控的基因。对Kaiso的进一步兴趣源于研究发现，其细胞质与细胞核的定位受到来自微环境的复杂信号的调控。

原文链接：

A role for Kaiso–p120ctn complexes in cancer?