Retinol Increases β-Catenin-RXRα Binding Leading to the Increased Proteasomal Degradation of β-Catenin and RXRα

Dillard, Alice; Lane, Michelle A.

doi:10.1080/01635580701586754

Cited by 17 publications

(17 citation statements)

References 25 publications

(56 reference statements)

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“…Thus, Nur77 could serve as a targeting molecule that carries its interacting proteins to certain cytoplasmic compartments for modification and degradation. Previous studies showed that RXRα, the Nur77 heterodimerization partner, could also target β-catenin for degradation through GSK3β and p53/Siah-independent mechanisms (Dillard and Lane 2007, Dillard and Lane 2008, Xiao et al 2003). Whether RXRα is involved in Nur77-mediated pathway remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77

et al. 2011

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Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including APC and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, plays a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is GSK3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA-binding and transactivation and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.

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Section: Discussionmentioning

confidence: 99%

Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77

et al. 2011

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“…Furthermore, while it is well-established that VDR heterodimerizes with RXR to exert transcriptional effects and promote cell differentiation (40), β-catenin also acts as a transcriptional co-activator of the RXR-VDR heterodimer resulting in increased transactivation of VDRE-driven genes in the presence of 1,25(OH) 2 D 3 , and causing enhanced antiproliferation (13, 41). Moreover, RXRα , an isoform expressed in the colonic epithelium, acts via agonists that enhance the interaction between RXR and β-catenin as well as increase the degradation of β-catenin (42, 43). RXR ligands have also been demonstrated to modify the antiproliferative response of 1,25(OH) 2 D 3 in two colon cancer cell lines, exhibiting an increased proliferative response in Caco-2 cells, but blocking it in HT-29 cells (44).…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in Vitamin D Receptor VDR/RXRA Influence the Likelihood of Colon Adenoma Recurrence

et al. 2010

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Low circulating levels of vitamin D affect colorectal cancer risk. The biological actions of the hormonal form of vitamin D, 1,25(OH) 2 D 3 , are mediated by the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptors (RXR). Using a single nucleotide polymorphism (SNP) tagging approach, we assessed the association between genetic variations in RXRA and VDR and odds of recurrent (metachronous) colorectal neoplasia in a pooled population of two studies. A total of 32 tag SNPs in RXRA and 42 in VDR were analyzed in 1,439 participants. A gene-level association was observed for RXRA and any (P = 0.04) or proximal (P = 0.03) metachronous neoplasia. No gene-level associations were observed for VDR, nor was any single SNP in VDR related to any metachronous adenoma after correction for multiple comparisons. In contrast, the association between RXRA SNP rs7861779 and proximal metachronous neoplasia was of borderline statistical significance [odds ratio (OR), 0.68; 95% confidence interval (95% CI), 0.53-0.86; unadjusted P = 0.001; adjusted P = 0.06], including when observed independently in each individual study. Haplotypes within linkage blocks of RXRA support an ∼30% reduction in odds of metachronous neoplasia arising in the proximal colon among carriers of specific haplotypes, which was strongest (OR proximal , 0.67; 95% CI, 0.52-0.86) for carriers of a CGGGCA haplotype (rs1805352, rs3132297, rs3132296, rs3118529, rs3118536, and rs7861779). Our results indicate that allelic variation in RXRA affects metachronous colorectal neoplasia, perhaps of particular importance in the development of proximal lesions.

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“…More recently, retinol treatment of colon cancer cells resulted in inhibition of cell migration and invasion [64]. Retinol also promoted proteosomal degradation of b-catenin and inhibited cell invasion by suppressing PI3K activity in colon cancer cells [65,66].…”

Section: Chemopreventive Mechanisms Of Carotenoidsmentioning

confidence: 98%

“…Reduces TNBS-induced colitis through decreasing levels of proinflammatory cytokines (TNF-a, IL-1b, and IL-17) in mice [63] Retinol Inhibits cell migration and invasion through decreasing gene expression and activities of MMPs [64] Decreases nuclear level and promotes proteosomal degradation of b-catenin [66] Inhibits cell invasion by suppression of PI3K activity [65] DHA Induces apoptosis, cell-cycle arrest and decreases colon cancer cell growth independent of p53 status [68] Suppresses arachidonic acid-induced cell proliferation, PGE 2 production, and COX-2 expression [69] Induces proteasome-dependent degradation of b-catenin and decreases its downstream gene MMP-7 and VEGF [70] Induces apoptosis through downregulation of Akt signaling [71] Conjugated linoleic acid Inhibits colon cancer growth through reducing phosphorylation of ERK1/2 and downstream c-myc [72] Decreases mRNA expression of TNF-a, IL-6, and IL-12 in human colonic epithelial Caco-2 cells [73] ERK1/2, extracellular signal-regulated protein kinase.…”

Section: All-trans-retinoic Acidmentioning

confidence: 99%

Molecular mechanisms for chemoprevention of colorectal cancer by natural dietary compounds

Pan

Lai

et al. 2010

Molecular Nutrition Food Res

158

135

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Colorectal cancer is one of the major causes of cancer-related mortality in both men and women worldwide. This review focuses on preventing the initiation and promotion of neoplastic growth in colorectal cancer, particularly with natural dietary compounds. Chemoprevention is defined as the use of natural dietary compounds and/or synthetic substances that can delay, prevent, or even reverse the development of adenomas, as well as the progression from adenoma to carcinoma. The molecular mechanisms of their chemopreventive action are associated with the modulation of signaling cascades, gene expressions involved in the regulation of cell proliferation, differentiation, and apoptosis and the suppression of chronic inflammation, metastasis, and angiogenesis. Here, we summarize the currently known targets and signaling pathways whereby natural dietary compounds interfere with the development of colorectal cancer, and thus providing evidence for these substances in colonic cancer chemopreventive action.

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Retinol Increases β-Catenin-RXRα Binding Leading to the Increased Proteasomal Degradation of β-Catenin and RXRα

Cited by 17 publications

References 25 publications

Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77

Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77

Genetic Polymorphisms in Vitamin D Receptor VDR/RXRA Influence the Likelihood of Colon Adenoma Recurrence

Molecular mechanisms for chemoprevention of colorectal cancer by natural dietary compounds

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