Cross-regulation of β-catenin–LEF/TCF and retinoid signaling pathways

AbstractVitamin A derivatives (retinoids) are potent regulators of embryogenesis, cell proliferation, epithelial cell differentiation and carcinogenesis [1]. In breast cancer cells, the effects of retinoids are associated with changes in the cadherin–β-catenin adhesion and signaling system [2,3]. β-catenin is a component of the Wnt signaling pathway, which regulates several developmental pathways [4]. Increases in cytoplasmic β-catenin and β-catenin signaling are also associated with numerous cancers, and are particularly important in colon cancer [5]. The oncogenic and developmental effects of β-catenin are mediated by its interaction with and activation of members of the LEF/TCF family of transcription factors [6–8]. Here, we shown that retinoic acid (RA) decreases the activity of the β-catenin–LEF/TCF signaling pathway. This activity of RA was independent of the adenomatous polyposis coli (APC) tumor suppressor and ubiquitination-dependent degradation of cytoplasmic β-catenin. Consistent with this finding, β-catenin interacted directly with the RA receptor (RAR) in a retinoid-dependent manner, but not with the retinoid X receptor (RXR), and RAR competed with TCF for β-catenin binding. The activity of RA on RAR-responsive promoters was also potentiated by β-catenin. The data suggest that direct regulation of β-catenin–LEF/TCF signaling is one mechanism whereby RA influences development, cell differentiation and cancer