Expression of a vitamin D-regulated gene (VDUP-1) in untreated- and MNU-treated rat mammary tissue

Yang, Xiaoqi; Young, Lindon H.; Voigt, Jeffrey M.

doi:10.1023/a:1005929714900

Cited by 44 publications

(26 citation statements)

References 23 publications

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“…A similar, but not so striking, suppressed VDR responsiveness was seen with the other two gene targets, which are more directly associated with antiproliferative VDR effects (20,(34)(35)(36)(37)(38). GADD45a mRNA expression patterns in MCF-12A cells showed significant peaks at 4 hours (1.4-fold; P < 0.05), which was sustained up to 8 hours; after which, a subsequent 2.1-fold increase occurred at 12 hours (P < 0.05) and decreased thereafter.…”

Section: Resultsmentioning

confidence: 56%

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Banwell¹,

MacCartney²,

Guy

et al. 2006

Clinical Cancer Research

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Purpose:We hypothesized that deregulated corepressor actions, with associated histone deacetylation activity, epigenetically suppressed vitamin D receptor (VDR) responsiveness and drives resistance towards 1a,25-dihydroxyvitamin D 3 . Experimental Design: Profiling, transcriptional, and proliferation assays were undertaken in 1a,25(OH) 2 D 3 -sensitive MCF-12A nonmalignant breast epithelial cells, a panel of breast cancer cell lines, and a cohort of primary breast cancer tumors (n = 21). Results: Elevated NCoR1 mRNA levels correlated with suppressed regulation of VDR target genes and the ability of cells to undergo arrest in G 1 of the cell cycle. A similar increased ratio of corepressor mRNA to VDR occurred in matched primary tumor and normal cells, noticeably in estrogen receptor a^negative (n = 7) tumors. 1a,25(OH) 2 D 3 resistance in cancer cell lines was targeted by cotreatments with either 1a,25(OH) 2 D 3 or a metabolically stable analogue (RO-26-2198) in combination with either trichostatin A (TSA; histone deacetylation inhibitor) or 5-aza-2V-deoxycytidine (DNA methyltransferase inhibitor). Combinations of vitamin D 3 compounds with TSA restored VDR antiproliferative signaling (target gene regulation, cell cycle arrest, and antiproliferative effects in liquid culture) to levels which were indistinguishable from MCF-12A cells. Conclusions: Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1a,25(OH) 2 D 3 resistance and seems to be particularly associated with estrogen receptor negativity.This lesion provides a novel molecular diagnostic and can be targeted by combinations of vitamin D 3 compounds and low doses of TSA.The nuclear receptor superfamily regulates diverse signals that are central to the formation and homeostasis of the mammary gland. The postgenomic description of the superfamily conjoined with profiling approaches (1) reveals that breast myoepithelial and epithelial cells express a rich cohort of nuclear receptors, many of which display overt nutrient-sensing capacity for micronutrients and macronutrients alongside the estrogen receptors (ERa and ERh; refs. 2 -6).Several of the diet-sensing nuclear receptors, such as the VDR, preferentially form heterodimers with retinoid X receptors whereas the ERs preferentially heterodimerize with one another. For the nuclear receptors to regulate transcriptional programs, these dimers must be contained as subunits in either large gene coactivator or corepressor complexes. In the absence of ligand, receptors exist in an apo state as part of large complexes (f2.0 MDa; ref. 7), associated with corepressors (e.g., NCoR1, NCoR2/SMRT, and TRIP15/Alien), and bound to response element sequences. These complexes actively recruit a range of enzymes that posttranslationally modify histone tails (e.g., histone deacetylases and methyltransferases) and thereby maintain a locally closed chromatin structure around response element sequences (8). Ligand binding induces a...

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Section: Resultsmentioning

confidence: 56%

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Banwell¹,

MacCartney²,

Guy

et al. 2006

Clinical Cancer Research

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“…1␣,25-dihydroxyvitamin D 3 induces myeloid cell differentiation (42), and inhibits fibroblast proliferation (43). In addition, mVDUP1 expression was decreased in rat mammary tumors, and up-regulation of mVDUP1 by 1␣,25-dihydroxyvitamin D 3 treatment inhibited tumor cell growth, having suggested the critical roles of mVDUP1 in mediating the inhibitory effects of 1␣,25-dihydroxyvitamin D 3 on tumor cell growth (44). In addition, a dominant-negative mutant TRX reverses the transformed phenotype of human breast cancer cells (15).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D3 Up-Regulated Protein 1 Mediates Oxidative Stress Via Suppressing the Thioredoxin Function

Junn

Han

et al. 2000

The Journal of Immunology

448

399

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As a result of identifying the regulatory proteins of thioredoxin (TRX), a murine homologue for human vitamin D3 up-regulated protein 1 (VDUP1) was identified from a yeast two-hybrid screen. Cotransfection into 293 cells and precipitation assays confirmed that mouse VDUP1 (mVDUP1) bound to TRX, but it failed to bind to a Cys32 and Cys35 mutant TRX, suggesting the redox-active site is critical for binding. mVDUP1 was ubiquitously expressed in various tissues and located in the cytoplasm. Biochemical analysis showed that mVDUP1 inhibited the insulin-reducing activity of TRX. When cells were treated with various stress stimuli such as H2O2 and heat shock, mVDUP1 was significantly induced. TRX is known to interact with other proteins such as proliferation-associated gene and apoptosis signal-regulating kinase 1. Coexpression of mVDUP1 interfered with the interaction between TRX and proliferation-associated gene or TRX and ASK-1, suggesting its roles in cell proliferation and oxidative stress. To investigate the roles of mVDUP1 in oxidative stress, mVDUP1 was overexpressed in NIH 3T3 cells. When cells were exposed to stress, cell proliferation was declined with elevated apoptotic cell death compared with control cells. In addition, c-Jun N-terminal kinase activation and IL-6 expression were elevated. Taken together, these results demonstrate that mVDUP1 functions as an oxidative stress mediator by inhibiting TRX activity.

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“…Published data suggest that TBP-2 may be involved in cell differentiation and apoptosis (Junn et al, 2000) and in cell proliferation and aging (Yoshida et al 2005). TBP-2 is also shown to have an anticancer role in mammary carcinomas (Young et al, 1996,Yang et al, 1998. Because of the important role of TRx in redox balance and lens clarity, it is essential to elucidate any regulation of the bioavailability of TRx that may be controlled by TBP-2.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)

Liyanage

Fernando

Lou

2007

Experimental Eye Research

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Thioredoxin (TRx) is known to control redox homeostasis in cells. In recent years, a specific TRx binding protein called thioredoxin binding protein-2 (TBP-2) was found in other cell types and it appeared to negatively regulate TRx bioavailability and thereby control TRx biological function. In view of the sensitivity of lens transparency to redox status, proper regulation of TRx bioavailability is of the utmost importance. This study was conducted to examine the presence and function of TBP-2 in human lens epithelial cells (HLE B3). We cloned human lens TBP-2 from a human cDNA library (GenBank accession number AY 594328) and showed that it is fully homologous to the human brain TBP-2 gene. The recombinant TBP-2 protein was partially purified and mass spectrometric analysis confirmed its sequence homology to that of brain TBP-2. Immunoprecipitates obtained from HLE B3 cells using anti-TRx and anti-TBP-2 antibodies showed the presence of TRx and TBP-2 in immunoprecipitates indicating the formation of a TRx-TBP-2 complex in vivo. Furthermore, under H 2 O 2 -stress conditions, TRx gene expression was transiently up-regulated while TBP-2 gene expression was inversely down-regulated as seen in both HLE B3 cells and in the epithelial cell layers from cultured pig lenses. Cells with overexpressed TBP-2 showed lower TRx activity, grew slower and were more susceptible to oxidative stress-induced apoptosis. This is the first report of the presence of a TRx-specific binding protein in the lens. Our data suggest that TBP-2 is likely a negative regulator for the bioavailability, and therefore, the overall function of TRx in the lens.

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Expression of a vitamin D-regulated gene (VDUP-1) in untreated- and MNU-treated rat mammary tissue

Cited by 44 publications

References 23 publications

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Vitamin D3 Up-Regulated Protein 1 Mediates Oxidative Stress Via Suppressing the Thioredoxin Function

Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)

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