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 ...

The life-cycle ofEchinostoma trivolvis (Cort, 1914) has been completed experimentally and the validity and identity of this species are discussed. Synonyms for cercariae and adults of E. trivolvis are as follows: Cercaria trivolvis

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