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Transcription Factor Encyclopedia  BETA
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Overview

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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References
  1. Daniel JM and Reynolds AB. The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol. Cell. Biol., 19(5):3614-23. (PMID 10207085)
  2. Kelly KF and Daniel JM. POZ for effect--POZ-ZF transcription factors in cancer and development. Trends Cell Biol., 16(11):578-87. (PMID 16996269)
  3. Iioka H et al. Kaiso is a bimodal modulator for Wnt/beta-catenin signaling. FEBS Lett., 583(4):627-32. (PMID 19166851)
  4. Kelly KF et al. Nuclear import of the BTB/POZ transcriptional regulator Kaiso. J. Cell. Sci., 117(Pt 25):6143-52. (PMID 15564377)
  5. Perez-Torrado R et al. Born to bind: the BTB protein-protein interaction domain. Bioessays, 28(12):1194-202. (PMID 17120193)
  6. Yoon HG et al. N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol. Cell, 12(3):723-34. (PMID 14527417)
  7. van Roy FM and McCrea PD. A role for Kaiso-p120ctn complexes in cancer? Nat. Rev. Cancer, 5(12):956-64. (PMID 16294216)
  8. Park JI et al. Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets. Dev. Cell, 8(6):843-54. (PMID 15935774)
  9. Daniel JM et al. The p120(ctn)-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides. Nucleic Acids Res., 30(13):2911-9. (PMID 12087177)
  1. Prokhortchouk A et al. The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev., 15(13):1613-8. (PMID 11445535)
  2. Kim SW et al. Isolation and characterization of XKaiso, a transcriptional repressor that associates with the catenin Xp120(ctn) in Xenopus laevis. J. Biol. Chem., 277(10):8202-8. (PMID 11751886)
  3. Spring CM et al. The catenin p120ctn inhibits Kaiso-mediated transcriptional repression of the beta-catenin/TCF target gene matrilysin. Exp. Cell Res., 305(2):253-65. (PMID 15817151)
  4. Soubry A et al. Expression and nuclear location of the transcriptional repressor Kaiso is regulated by the tumor microenvironment. Cancer Res., 65(6):2224-33. (PMID 15781635)
  5. Reynolds AB. p120-catenin: Past and present. Biochim. Biophys. Acta, 1773(1):2-7. (PMID 17175391)
  6. Thoreson MA et al. Selective uncoupling of p120(ctn) from E-cadherin disrupts strong adhesion. J. Cell Biol., 148(1):189-202. (PMID 10629228)
  7. Kelly KF et al. NLS-dependent nuclear localization of p120ctn is necessary to relieve Kaiso-mediated transcriptional repression. J. Cell. Sci., 117(Pt 13):2675-86. (PMID 15138284)
  8. Ogden SR et al. p120 and Kaiso regulate Helicobacter pylori-induced expression of matrix metalloproteinase-7. Mol. Biol. Cell, 19(10):4110-21. (PMID 18653469)
Figures
FIGURE 1 Kaiso and the Wnt Signaling System
Kaiso belongs to a network of signaling molecules that regulate gene expression in response to extracellular signals. Kaiso inhibits expression of Wnt target genes such as Cyclin D1, MMP7, Wnt11, and siamois. p120 translocates to the nucleus, via a yet unidentified mechanism, and its interaction with Kaiso relieves Kaiso-mediated repression of its target genes.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.