Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways.
Vitamin 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-beta-catenin adhesion and signaling system [2] [3]. beta-catenin is a component of the Wnt signaling pathway, which regulates several developmental pathways [4]. Increases in cytoplasmic beta-catenin and beta-catenin signaling are also associated with numerous cancers, and are particularly important in colon cancer [5]. The oncogenic and developmental effects of beta-catenin are mediated by its interaction with and activation of members of the LEF/TCF family of transcription factors [6] [7] [8]. Here, we shown that retinoic acid (RA) decreases the activity of the beta-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 beta-catenin. Consistent with this finding, beta-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 beta-catenin binding. The activity of RA on RAR-responsive promoters was also potentiated by beta-catenin. The data suggest that direct regulation of beta-catenin-LEF/TCF signaling is one mechanism whereby RA influences development, cell differentiation and cancer.
Easwaran
V
V
Departments of Oncology and Cell Biology, The Lombardi Cancer Center, Georgetown University, Washington D.C., 20007, USA.
Pishvaian
M
M
Salimuddin
Byers
S
S
D018938:Caco-2 Cells; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D009154:Mutation; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014452:Ubiquitins / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014452:Ubiquitins; D051176:beta Catenin; D014212:Tretinoin