Characterization ofthe Cell Cycle Regulator, CCND1, as a Kaiso Target Gene.

Abstract

Kaiso is a novel member of the BTB/POZ (Broad complex, Tramtrak, Bric a brac,/Pox virus and zinc finger) zinc finger family of transcriptional regulators that have many roles in development and tumorigenesis. Kaiso was first identified as a binding partner for p 120ctn, an Armadillo catenin with roles in cell adhesion and stabilization of cadherins at the cell membrane. Kaiso is both an activator and repressor of gene transcription and interacts with two distinct types of DNA sequence; a consensus Kaiso binding site (KBS) TCCTGCNA and methylated CpG dinucleotide pairs (i.e. CpGCpG). Thus far p120's nuclear role is to inhibit Kaiso-mediated regulation of its target genes. Some of the Kaiso target genes identified to date include, matrilysin, rapsyn, and MTA2. The Kaiso homologue in Xenopus laevis (frog) has also been shown to regulate the cell cycle regulator CCND 1. Sequence analysis of the human CCND1 promoter revealed several potential Kaiso binding elements including both KBS and methylatable CpGs. My research demonstrated that Kaiso binds to the CCND1 promoter in vitro and in vivo to both KBS-specific and CpG-specific regions. Furthermore, I determined that Kaiso may act as either a repressor or activator of the human CCND 1 gene depending on the cellular environment. Altogether these data support my hypothesis that Kaiso is a regulator of the CCND1 gene. Future studies looking at the significance of KBS versus CpG-binding on Kaiso's mechanism of regulation are required to determine the significance of this regulation. Furthermore, studies examining the cell cycle-dependent changes in Kaiso levels may reveal how alterations in Kaiso expression affect Kaiso target genes including CCND1.