Glycogen synthase kinase-3β regulates ΔNp63 gene transcription through the β-catenin signaling pathway

Overexpression of Delta Np63 has been observed in a number of human cancers, suggesting a role for Delta Np63 in carcinogenesis. In the present study, we show that inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) by lithium chloride (LiCl) elicited a stimulatory effect on Delta Np63 promoter activity in HEK 293T cells. Exposure to LiCl induced Delta Np63 promoter activation as well as Delta Np63 protein expression in the cells. The effect of GSK-3 beta on Delta Np63 expression was further confirmed by the use of two highly specific GSK-3 beta inhibitors, SB216763 and SB415286. Further study showed the presence of a putative beta-catenin responsive element (beta-catenin-RE) in the Delta Np63 promoter region, and the stimulation of Delta Np63 promoter activity by GSK-3 beta inhibitor is markedly abolished by mutation or deletion of the putative P-catenin-RE. Data are also presented to show that beta-catenin acts together with Lef-1 to influence Delta Np63 promoter activity and protein expression.