The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.
1alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] regulates calcium homeostasis and controls cellular differentiation and proliferation. The vitamin D receptor (VDR) is a ligand-regulated transcription factor that recognizes cognate vitamin D response elements (VDREs) formed by direct or everted repeats of PuG(G/T)TCA motifs separated by 3 or 6 bp (DR3 or ER6). Here, we have identified direct 1,25(OH)2D3 target genes by combining 35,000+ gene microarrays and genome-wide screens for consensus DR3 and ER6 elements, and DR3 elements containing single nucleotide substitutions. We find that the effect of a nucleotide substitution on VDR binding in vitro does not predict VDRE function in vivo, because substitutions that disrupted binding in vitro were found in several functional elements. Hu133A microarray analyses, performed with RNA from human SCC25 cells treated with 1,25(OH)2D3 and protein synthesis inhibitor cycloheximide, identified more than 900 regulated genes. VDREs lying within -10 to +5 kb of 5'-ends were assigned to 65% of these genes, and VDR binding was confirmed to several elements in vivo. A screen of the mouse genome identified more than 3000 conserved VDREs, and 158 human genes containing conserved elements were 1,25(OH2)D3-regulated on Hu133A microarrays. These experiments also revealed 16 VDREs in 11 of 12 genes induced more than 10-fold in our previous microarray study, five elements in the human gene encoding the epithelial calcium channel TRPV6, as well as novel 1,25(OH2)D3 target genes implicated in regulation of cell cycle progression. The combined approaches used here thus provide numerous insights into the direct target genes underlying the broad physiological actions of 1,25(OH)2D3.
Importantly, this synergistic response was also seen in macrophages from a donor wild type for NOD2 but was absent in macrophages from patients with Crohn disease homozygous for non-functional NOD2 variants. These studies provide strong molecular links between vitamin D deficiency and the genetics of Crohn disease, a chronic incurable inflammatory bowel condition, as Crohn's pathogenesis is associated with attenuated NOD2 or DEFB2/HBD2 function.
Atrazine is the most commonly detected pesticide contaminant of ground water, surface water, and precipitation. Atrazine is also an endocrine disruptor that, among other effects, alters male reproductive tissues when animals are exposed during development. Here, we apply the nine so-called “Hill criteria” (Strength, Consistency, Specificity, Temporality, Biological Gradient, Plausibility, Coherence, Experiment, and Analogy) for establishing cause–effect relationships to examine the evidence for atrazine as an endocrine disruptor that demasculinizes and feminizes the gonads of male vertebrates. We present experimental evidence that the effects of atrazine on male development are consistent across all vertebrate classes examined and we present a state of the art summary of the mechanisms by which atrazine acts as an endocrine disruptor to produce these effects. Atrazine demasculinizes male gonads producing testicular lesions associated with reduced germ cell numbers in teleost fish, amphibians, reptiles, and mammals, and induces partial and/or complete feminization in fish, amphibians, and reptiles. These effects are strong (statistically significant), consistent across vertebrate classes, and specific. Reductions in androgen levels and the induction of estrogen synthesis – demonstrated in fish, amphibians, reptiles, and mammals – represent plausible and coherent mechanisms that explain these effects. Biological gradients are observed in several of the cited studies, although threshold doses and patterns vary among species. Given that the effects on the male gonads described in all of these experimental studies occurred only after atrazine exposure, temporality is also met here. Thus the case for atrazine as an endocrine disruptor that demasculinizes and feminizes male vertebrates meets all nine of the “Hill criteria”.
SignificanceEpidemiological evidence suggests that vitamin D can protect women from developing breast cancer (BC). This study reveals that vitamin D and its receptor regulate autophagy in both normal mammary epithelial cells and luminal BCs, and suggests a potential mechanism underlying the link between vitamin D levels and BC risk. In addition, this work suggests that vitamin D receptor ligands could be exploited therapeutically for the treatment of a significant subset of BCs.
Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell-and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC-regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push-pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr −/− mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.V itamin D is obtained naturally from limited dietary sources. It is also generated by cutaneous conversion of 7-dehydrocholesterol in the presence of adequate surface solar UV-B radiation, which varies with latitude and time of year (1). Vitamin D has attracted broad clinical interest because insufficiency or deficiency is widespread in several populations worldwide (2-4). Although initially identified as a regulator of calcium homeostasis, vitamin D is now known to have a broad spectrum of actions, driven by the virtually ubiquitous expression of the vitamin D receptor (VDR), a nuclear receptor and hormone-regulated transcription factor. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell-cycle arrest and nonmalignant and malignant cell differentiation (5-11). Epidemiological data have provided associations between lack of UV-B exposure, vitamin D insufficiency, and the prevalence of certain cancers (12). A large prospective study associated vitamin D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers [head and neck squamous cell carcinoma (HNSCC), esophageal, pancreatic, stomach, and colorectal cancers] and leukemias (13). VDR gene polymorphi...
Vitamin D is obtained from limited dietary sources and UVB-stimulated photoconversion of 7-dehydrocholesterol in skin (36). Hepatic hydroxylation catalyzed by CYP27A1, CYP2R1, and possibly other enzymes generates the major circulating metabolite 25-hydroxyvitamin D (25D). 25D is a relatively long-lived metabolite and is a marker of vitamin D status. 25D is 1␣ hydroxylated in kidney and peripheral tissues to produce hormonal 1,25-dihydroxyvitamin D (1,25D). While renal 1␣ hydroxylation generates much of the circulating 1,25D, extrarenal 1␣ hydroxylation is a critical source of 1,25D in situ in a number of tissues (61). Moreover, while renal CYP27B1 expression/activity is regulated by calcium homeostatic signals (e.g., parathyroid hormone), extrarenal 1␣ hydroxylation is regulated by distinct physiological inputs.1,25D binds the nuclear vitamin D receptor (VDR), which heterodimerizes with related retinoid X receptors (RXRs) to recognize vitamin D response elements (VDREs) in target genes (36). Although initially identified as a regulator of calcium homeostasis, 1,25D is now known to have a broad spectrum of actions. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell cycle arrest and nonmalignant and malignant cell differentiation (14,24,27,34,35,37,46,49). Moreover, epidemiological data provide associations between lack of UVB exposure, vitamin D insufficiency, and the prevalence of certain cancers (16). Notably, a large prospective study associated 25D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers (head and neck squamous cell carcinoma [HNSCC] and esophageal, pancreatic, stomach, and colorectal cancers) and leukemias (23). VDR gene polymorphisms also correlate with protection against different malignancies, including HNSCC (16, 39). The above is noteworthy, as numerous studies have shown that vitamin D insufficiency or deficiency is widespread in temperate populations (26,61).FoxO1, FoxO3a, FoxO4, and FoxO6 transcription factors regulate cell proliferation, differentiation, and metabolism and control longevity (1,10,21,25,52). Serial ablation in mice of genes encoding FoxO proteins revealed that these proteins are bona fide tumor suppressors (7,17,28). FoxO function is inhibited by mitogen-activated PI3 kinase, which stimulates Akt-dependent phosphorylation, nuclear export (1, 10, 25), and proteasomal degradation (17,28). FoxOs are also regulated by acetylation, which can be reversed by the NAD-dependent sirtuin 1 (Sirt1) class III lysine deacetylase (15,30). Acetylation reduces DNA binding and enhances phosphorylation and inactivation (43). Notably, FoxO and c-MYC target genes partially overlap, and FoxO factors repress a subset of c-MYC-induced genes, including CCND2, which encodes cyclin D2 (18,52).We have been interested in understanding the mechanisms regulating the anticancer properties of vitamin D, in particular the molecular genetic events underlying its control of cell proliferation. We noted that there ...
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