Trans-repression of β-Catenin Activity by Nuclear Receptors

Abstract

The signaling/oncogenic activity of ␤-catenin can be repressed by the activation of nuclear receptors such as the vitamin A, vitamin D, and androgen receptors. Although these receptors directly interact with ␤-catenin and can sequester it away from its transcription factor partner T-cell factor, it is not known if this is the mechanism of trans-repression. Using several different promoter constructs and nuclear receptors and mammalian two-hybrid and mutation analyses we now show that interaction with the co-activator, p300, underlies the trans-repression of ␤-catenin signaling by nuclear receptors and their ligands.By definition, the term chemoprevention refers to the treatment of individuals with premalignant lesions, individuals who are predisposed to the development of malignant lesions, and individuals early in the process of carcinogenesis, with the intention of preventing the later stages of carcinogenesis from developing (1). Although chemopreventative agents such as vitamins A and D are often effective in this context there is no de facto reason to assume that the same treatment would not be effective in more advanced stages of carcinogenesis. Nevertheless, this is often not the case because many advanced cancers in vivo and de-differentiated carcinoma cells in vitro are refractory to the anti-tumor, growth inhibitory activities of vitamins A and D. Thus, not only do more malignant tumors and cells have defects in the expression and function of several molecules characteristic of differentiated epithelial cells; they are also less responsive to differentiating agents. An obvious question arises from this realization; what are the molecular mechanisms that underlie resistance to vitamins A and D? In some cases, resistance is because of a defect in particular nuclear receptor isoforms. However, some cells, which are not growth-inhibited by vitamin A, express normal retinoic acid receptors (RARs) 1 /RXRs and retain the ability to up-regulate retinoid-sensitive genes (2). These data indicate that other molecules such as components of the cadherin/␤-catenin-based signaling and adhesion system may also need for retinoic acid to exert its anti-proliferative effects (3, 4).Recently, several studies show that the signaling/oncogenic activity of ␤-catenin is trans-repressed by the activation of nuclear receptors such as RAR, vitamin D receptor (VDR), and androgen receptors (AR) (3, 5). In addition to its role in cell-cell adhesion ␤-catenin acts as a co-activator for the TCF/lymphoid enhancer factor (LEF) family of transcription factors. Although it is possible that all of these receptors directly interact with ␤-catenin and sequester it away from TCF, it is not known if this is the mechanism of trans-repression. Nuclear receptors also trans-repress AP-1, serum response factor (SRF), and NFB activity by a mechanism likely involving interaction with a common pool of co-activators rather than a direct interaction with transcription factors (6 -8). On the other hand, in contrast to AP-1, high levels of ␤-catenin mark...

A direct protein-protein interaction is involved in the suppression of β-catenin transcription by retinoid X receptor α in colorectal cancer cells

“…[25][26][27] But, most studies reported that nuclear receptors repressed β-catenin signaling in the presence of ligand or agonist. 16,17,23,24 However, our data in the first time demonstrated that RXRα overexpression directly inhibited endogenous and exogenous β-catenin transcriptional activity and expression in the absence of RXR agonist. However, the inhibition was abrogated by targeted RXRα small RNA interfering.…”

“…21,22 Recently, several lines of evidence showed that nuclear receptors affected β-catenin/TCF/LEF-mediated gene transcription and β-catenin protein. For example, retinoid-activated RAR acts as a potent repressor of β-catenin/TCF signaling in retinoid-sensitive colorectal cancer cells, 16,17,23,24 and activation of the vitamin D receptor with its metabolite ligand, 1α,25(OH) 2 vitamin D 3 , could repress Wnt/β-catenin/TCF signaling. [25][26][27] But, most studies reported that nuclear receptors repressed β-catenin signaling in the presence of ligand or agonist.…”

Peroxisome Proliferator-activated Receptor γ Activation Can Regulate β-Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway

“…Western analysis was performed utilizing antibodies against ␤-catenin and actin. tors pathways (including vitamins A and D and androgen receptors) required the N-terminal 1-151 amino acids of ␤-catenin and involved the participation of the coactivator p300 (71). A similar mechanism might be activated following stimulation of PPAR␥, because the PPAR␥2-mediated pathway of ␤-catenin degradation also involved the N-terminal (1-131 amino acids) fragment of ␤-catenin.…”

Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells?

“…An active form of vitamin D, 1α,25-dihydroxyvitamin D3, and its synthetic derivatives have shown chemopreventive effects in animal models of colorectal and breast cancers. Although the mechanism by which vitamins inhibit Wnt/β-catenin signaling pathway is not fully understood, it is suggested that activated nuclear receptors for vitamins interact with β-catenin and compete with TCFs (70,71). Recently it has also been suggested that both vitamin A and D might induce Wnt/β-catenin inhibitory proteins, e.g., Disabled-2 (Dab2) by retinoic Polyphenols.…”