Butyrate and vitamin D 3 induce transcriptional attenuation at the cyclin D1 locus in colonic carcinoma cells

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10467, USA.
Journal of Cellular Physiology (Impact Factor: 3.84). 03/2009; 218(3):638-42. DOI: 10.1002/jcp.21642
Source: PubMed


In stimulating maturation of colonic carcinoma cells, the short chain fatty acid butyrate, and 1alpha,25-dihydroxyvitamin D(3), were shown to attenuate transcription of the cyclin D1 gene, giving rise to truncated transcripts of this locus. Moreover, a sequence which is highly conserved in the human, mouse, rat, and dog genome was found in the 4 kb long intron 3 of the human cyclin D1 gene, and is capable of forming a hairpin structure similar to that of microRNA precursors. The expression of this sequence is also decreased by the attenuation. Thus, the transcriptional attenuation at the cyclin D1 locus not only down-regulates the expression of this key gene in mucosal cell maturation and tumorigenesis, but may also abrogate the generation of a molecule that encompasses this conserved sequence in cyclin D1 intron 3.


Available from: Stefan Roepcke, Jun 30, 2014
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    • "In various cell culture models, however, butyrate inhibits proliferation, a result that has been linked either to the downregulation of cyclin D1 (Maier et al., 2009) or to the downregulation of the cyclin-dependent kinases (CDK) that overrule the concurrent increases in Dtype cyclins (Mathew et al., 2010). As D-type cyclins and their target kinases are responsible for G (gap) 0 /G 1 to S (synthesis) phase progression, the downregulation of either could plausibly explain the antiproliferative effect of butyrate in vitro. "
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    ABSTRACT: We tested the hypothesis that the proliferative effects of intraruminal butyrate infusions on the ruminal epithelium are linked to upregulation in cyclin D1 (CCND1), the cyclin-dependent kinase 4 (CDK4), and their possible association with enhanced absorption of short-chain fatty acids (SCFA). Goats (n = 23) in 2 experiments (Exp.) were fed 200 g/d concentrate and hay ad libitum. In Exp. 1, goats received an intraruminal infusion of sodium butyrate at 0.3 (group B, n = 8) or 0 (group C, n = 7) g/kg of body weight (BW) per day before morning feeding for 28 d and were slaughtered 8 h after the butyrate infusion. In Exp. 2, goats (n = 8) received butyrate infusion and feeding as in Exp. 1. On d 28, epithelial samples were biopsied from the antrium ruminis at 0, 3, and 7 h after the last butyrate infusion. In Exp. 1, the ruminal molar proportional concentration of butyrate increased in group B by about 110% after butyrate infusion and remained elevated for 1.5 h; thereafter, it gradually returned to the baseline (preinfusion) level. In group C, the molar proportional concentration of butyrate was unchanged over the time points. The length and width of papillae increased in B compared with C; this was associated with increased numbers of cells and cell layers in the epithelial strata and an increase in the surface area of 82%. The mRNA expression of CCND1 increased transiently at 3 h but returned to the preinfusion level at 7 h following butyrate infusion in Exp. 2. However, it did not differ between B and C in Exp. 1, in which the ruminal epithelium was sampled at 8 h after butyrate infusion. The mRNA expression of the monocarboxylate transporter MCT4, but not MCT1, was stably upregulated in B compared with C. The estimated absorption rate of total SCFA (%/h) increased in B compared with C. We conclude that transient increases in cyclin D1 transcription contribute to butyrate-induced papillae growth and subsequently to the increased absorption of SCFA in the ruminal epithelium of goats.
    Journal of Dairy Science 10/2013; 96(12). DOI:10.3168/jds.2013-6700 · 2.57 Impact Factor
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    • "In line with this finding, we report that c-fos, a gene under the control of AP-1, showed similar pattern of super-induction, while it was not observed for cyclin D1. Butyrate was shown to attenuate cyclin D1 [41], [45] and decrease the level of other genes linked to cell proliferation such as cdk1 as well as inducing differentiation-specific genes including transglutaminase type I [46]. Moreover, butyrate was shown to induce c-fos and c-jun in cancer cell lines [47]. "
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    PLoS ONE 12/2012; 7(12):e52869. DOI:10.1371/journal.pone.0052869 · 3.23 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that the persistent exposure of human bronchial epithelial cells to nicotine (Nic) through nicotinic acetylcholine receptors increases cyclin D1 promoter activity and protein expression. The main purpose of this study is to elucidate the carcinogenic role of cyclin D3, which is involved in breast tumorigenesis when induced by Nic. Real-time PCR analysis revealed that cyclin D3 is highly expressed at the mRNA level in surgically dissected breast tumor tissue, compared to the surrounding normal tissue (tumor/normal fold ratio = 17.93, n = 74). To test whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells, the transformed cell line MCF-10A-Nic (DOX) was generated from normal breast epithelial cells (MCF-10A) with inducible α9-nAChR gene expression, using the adenovirus tetracycline-regulated Tet-off system. Tet-regulated overexpression of α9-nAChR in MCF-10A-Nic (DOX) xenografted BALB/c-nu/nu mice resulted in a significant induction of cyclin D3. In contrast, cyclin D3 expression was down-regulated in α9-nAChR knock-down (siRNA) MDA-MB-231-xenografted tumors in NOD.CB17-PRKDC(SCID)/J(NOD-SCID) mice. Furthermore, we found that Nic-induced human breast cancer (MDA-MB-231) cell proliferation was inhibited by 1 μM of garcinol (Gar), isolated from the edible fruit Garcinia indica, through down-regulation of α9-nAChR and cyclin D3 expression. These results suggest that α9-nAChR-mediated cyclin D3 overexpression is important for nicotine-induced transformation of normal human breast epithelial cells. The homeostatic regulation of cyclin D3 has the potential to be a molecular target for antitumor chemotherapeutic or chemopreventive purposes in clinical breast cancer patients.
    Breast Cancer Research and Treatment 03/2010; 125(1):73-87. DOI:10.1007/s10549-010-0821-3 · 3.94 Impact Factor
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