ZBTB33, referred to as Kaiso in the literature, belongs to the BTB/POZ-ZF family of transcription factors that are commonly misregulated in various cancers^[1][2]. Kaiso was first identified in a yeast two-hybrid screen as a binding partner for the catenin and Src kinase substrate p120^[1]. Kaiso is a typical member of the BTB/POZ-ZF family and possesses an N-terminal protein-protein interaction BTB/POZ domain and a C-terminal DNA-binding zinc finger domain^[1][2]. Surprisingly, Kaiso’s interaction with p120 is mediated via a region just outside its zinc finger domain rather than via its BTB/POZ domain^[3]. Like other members of the BTB/POZ-ZF family, e.g. PLZF, BCL-6, HIC1, and ZBTB7, Kaiso exhibits transcriptional repressor activity mediated through its BTB/POZ domain^[4][5]. Kaiso interacts directly with NCoR via its BTB/POZ domain, which then recruits co-repressor complexes containing SMRT, NCoR, mSin3A, and HDAC^[5][6]. Transcriptional repression by Kaiso is hypothesized to occur through local chromosomal changes that convert chromatin from an active “open” state to a repressed “closed” state^[7]. NCoR, SMRT, mSin3A, and HDACs are the proposed mediators of chromosomal remodeling and subsequent silencing of Kaiso target genes^[8][6]. Kaiso is unique among the BTB/POZ-ZF family in that it binds both a sequence-specific Kaiso binding site (KBS) and methylated CpG dinucleotide pairs in target gene promoters^[9][10]. Some cellular targets of Kaiso-mediated repression include MTA2, Cyclin-D1, MMP-7, and Wnt11^{[9][11][8][10][12]}. In both cultured cells and normal tissue, Kaiso exhibits strong, diffuse nuclear localization but several studies report that Kaiso expression and localization is dynamic and may be dependent on the tumor microenvironment^[13]. Tumor xenografts into nude mice show that Kaiso is localized in the cytoplasm of cells at the hypoxic tumor center, suggesting that Kaiso’s localization may be altered in response to hypoxic stress^[13]. Studies have also shown that the expression and subcellular localization of p120 can affect Kaiso’s subcellular localization^{[2][4][12][7]}. p120 is found primarily at the cell membrane of epithelial cells where it regulates E-cadherin stability and turnover^[14][15]. Upon dissociation from E-cadherin, p120 translocates to the nucleus where it interacts with Kaiso^[16][12][7]. Upon interaction with p120, Kaiso is dislodged from its target genes^[12]. The result is a de-repression of Kaiso target genes and this derepression is particularly relevant to Helicobacter pylori-induced gastric cancer^[17][12]. Specifically, upregulation of the Kaiso target MMP-7 correlates with initiation of adenocarcinoma development in H. pylori-induced gastric cancer^[17]. H. plylori strains possessing the cytotoxin-associated gene (cag) pathogenicity island have been shown to selectively increase MMP-7 transcript and protein levels in the gastric epithelium^[17]. Recent findings indicate that cag+ H. pylori strains cause aberrant p120 translocation to the nucleus where it relieves Kaiso-mediated repression of MMP-7; this increase in MMP-7 expression ultimately contributes to the development of gastric cancer^[17].

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