P120-Catenin Isoforms 1 and 3 Regulate Proliferation and Cell Cycle of Lung Cancer Cells via β-Catenin and Kaiso Respectively

Abstract

BackgroundThe different mechanisms involved in p120-catenin (p120ctn) isoforms' 1/3 regulation of cell cycle progression are still not elucidated to date.Methods and FindingsWe found that both cyclin D1 and cyclin E could be effectively restored by restitution of p120ctn-1A or p120ctn-3A in p120ctn depleted lung cancer cells. When the expression of cyclin D1 was blocked by co-transfection with siRNA-cyclin D1 in p120ctn depleted cells restoring p120ctn-1A or 3A, the expression of cyclin E was slightly decreased, not increased, implying that p120ctn isoforms 1 and 3 cannot up-regulate cyclin E directly but may do so through up-regulation of cyclin D1. Interestingly, overexpression of p120ctn-1A increased β-catenin and cyclin D1 expression, while co-transfection with siRNA targeting β-catenin abolishes the effect of p120ctn-1A on up-regulation of cyclin D1, suggesting a role of β-catenin in mediating p120ctn-1A's regulatory function on cyclin D1 expression. On the other hand, overexpression of p120ctn isoform 3A reduced nuclear Kaiso localization, thus decreasing the binding of Kaiso to KBS on the cyclin D1 promoter and thereby enhancing the expression of cyclin D1 gene by relieving the repressor effect of Kaiso. Because overexpressing NLS-p120ctn-3A (p120ctn-3A nuclear target localization plasmids) or inhibiting nuclear export of p120ctn-3 by Leptomycin B (LMB) caused translocation of Kaiso to the nucleus, it is plausible that the nuclear export of Kaiso is p120ctn-3-dependent.ConclusionsOur results suggest that p120ctn isoforms 1 and 3 up-regulate cyclin D1, and thereby cyclin E, resulting in the promotion of cell proliferation and cell cycle progression in lung cancer cells probably via different protein mediators, namely, β-catenin for isoform 1 and Kaiso, a negative transcriptional factor of cyclin D1, for isoform 3.

Kaiso Interacts with p120-Catenin to Regulate β-Catenin Expression at the Transcriptional Level

“…Our previous study demonstrated that Kaiso binds to p120ctn in lung cancer cells, and that p120ctn 3 is likely to be the major isoform [24], [25], [26]. However, we did not confirm that p120ctn isoform 1A combines with Kaiso.…”

The POZ-ZF Transcription Factor Kaiso (ZBTB33) Induces Inflammation and Progenitor Cell Differentiation in the Murine Intestine

“…Surprisingly, Ki67 expression was decreased in Line A mice and Ki67 positive cells were localized more apical to the normal crypt/villus boundary (Figure 6A). We next evaluated the expression of the Kaiso target gene cyclin D1 [4], [21] that has been shown to drive proliferation in the intestinal epithelium and is frequently overexpressed in colon cancer [35]. Similar to Ki67, Cyclin D1 expression was also decreased in Line A Kaiso Tg/+ mice but surprisingly the apparent decreased numbers of Cyclin D1 positive (+) cells in Kaiso Tg/+ intestines was not statistically significant (Figure 6B, C).…”

“…Since its discovery as a binding partner for the Src kinase substrate and cell adhesion protein p120 ctn , mounting evidence suggests that the POZ-ZF transcription factor Kaiso functions in vertebrate development and tumorigenesis [1], [2], [3], [4], [5], [6], [7], [8]. To date however, Kaiso’s role in these processes in mammalian systems remains unclear, and much controversy surrounds several aspects of Kaiso’s function; this includes the mechanism by which it binds DNA [9], [10], [11], [12], [13], [14], [15], [16], [17] and its function in regulating the canonical Wnt signalling pathway that plays a key role in vertebrate development and tumorigenesis [8], [11], [14], [18], [19].…”

Beyond β-catenin: prospects for a larger catenin network in the nucleus

“…Although this limited number does not indicate larger roles for Kaiso in conjunction with p120 catenin, surprising findings have arisen. In particular, the control regions of a number of mammalian or X. laevis Kaiso target genes (for example, those encoding matrilysin, cyclin D1, WNT11 and Siamois) are regulated not only by Kaiso 45,79–85 but also by β-catenin and TCF 86,87,88 . Indeed, although different underlying mechanisms have been proposed 73 , the TCF and Kaiso repressors biochemically associate, their derepression is coordinated at gene control regions and their functional interrelationship has been shown in vivo 45,79 .…”