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Background.

Vitamin D was first identified as a cure for nutritional rickets, a disease of bone growth caused by an inadequate uptake of dietary calcium. Cod liver oil was discovered as an excellent source of anti-rachitic activity in 1827, although it wasn鈥檛 until several decades later that the active ingredient was identified as vitamin D3. Even earlier, in 1822, a Polish physician experimenting with children reached the remarkable conclusion that sunlight cured rickets. It is now known that secosteroidal vitamin D3 is produced in skin via photochemical and thermal conversion of 7-dehydrocholesterol in the presence of UVB light. UVB irradiation is absorbed by atmospheric ozone; consequently, surface UVB varies markedly in intensity with latitude and time of year. At the latitude of Montreal UVB intensity is sufficient to make vitamin D in skin during 6 months of the year. Moreover, as vitamin D intake is generally inadequate in most diets, vitamin D insufficiency or deficiency rises in frequency with increasing latitude. Epidemiological studies link vitamin D deficiency to increased rates of听cancer, as well as听颈尘尘耻苍别听补苍诲听infectious diseases. U.S. rates of bladder, breast, colon, ovary and rectal cancer increase 2-fold from south to north and north-south gradients of immune conditions such as听multiple sclerosis,听type 1 diabetes听补苍诲听Crohn鈥檚 disease听have been documented.

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Much of the action of 1,25D can be explained by its binding to and activation of the vitamin D receptor (VDR). The VDR is a ligand-activated transcription factor composed of a highly conserved DNA binding domain, and an 伪-helical ligand binding domain.

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To find out more about vitamin D and the VDR, read our article in Scientific American [view PDF format].

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Project 1(ii). Investigating the anticancer properties of vitamin D.

Identifying 1,25D target genes underlying its anticancer effects.听For the last several years, we have been analyzing the potential of analogs of vitamin D3 as potential agents of cancer chemoprevention. We have found treatment of squamous carcinoma cells with a vitamin D analog induces expression of several markers of squamous cell differentiation, and suppresses markers of squamous carcinoma progression听in vitro听补苍诲听in vivo. (J. Nat. Cancer Inst. 2001 [view PDF format]). We have been focusing on the molecular events underlying cell cycle arrest by vitamin D signaling and have found that the VDR controls cell cycle progression in part by inducing the function of FoxO transcription factors, cell cycle inhibitors 补苍诲听bona fide听tumor suppressors (Mol. Cell Biol., 2010 [view PDF format]). More recently we showed that vitamin D signaling through the VDR controls control expression and function of cMYC, an oncogenic transcription factor that drives cell cycle progression. Vitamin D signaling dramatically reduced total cMYC levels and dramatically enhanced the expression of its antagonist the transcriptional repressor MXD1, leading to inhibition of target gene expression (PNAS 2012 [view PDF format]).

Ablation of FBW7 expression attenuates 1,25D-induced turnover of c-MYC expression

Project 3. Structure/function studies of LCoR, a corepressor of gene expression.

We identified a novel nuclear factor that we called ligand-dependent corepressor (Mol. Cell, 2003 [view PDF format]). LCoR was identified as a protein that interacted with the ligand-bound estrogen receptor, which is a nuclear receptor and hormone-regulated transcription factor. This finding was remarkable as agonist-bound nuclear receptors usually recruit coactivators of transcription. LCoR represses ligand-dependent transcription by several steroid and non-steroid nuclear receptors. It binds to ligand-bound steroid receptors in vitro via a single 鈥渘uclear receptor鈥� (NR) box, an amphipathic alpha helix containing the motif LXXLL. Mutation of this motif abolishes binding of LCoR to ligand-bound receptors, and disrupts its repressor activity. Mutagenesis of the estrogen receptor ligand binding domain identified a broad surface of interaction with LCoR centered on the coactivator binding pocket.

LCoR is widely expressed in the adult and throughout fetal development. Highest levels are found in the placenta, where most of LCoR is expressed in the syncytiotrophoblast layer, a critical interphase of maternal and fetal circulation and an important site of steroid hormone signaling.

Much of our effort on LCoR has focused on identifying its interacting partners. We found that LCoR functioned as a corepressor at least in part by recruiting HDACs and the corepressors CtBP (C-terminal binding protein) and its interacting partner CtIP (JBC 2009a and 2009b). More recently, we discovered that LCoR also interacts with other classes of transcription factors, notably the transcriptional repressor Kruppel-like factor 6 (KLF6) (JBC, 2012 [view pdf format]). Moreover, it also interacts with another corepressor Kruppel-associated protein 1 (KAP-1) and KAP-1-associated transcription factors to repress gene transcription (Nucleic Acids Research 2014). Our currents efforts are aimed at using high-throughput proteomics, bioinformatics and functional genomics to characterize the LCoR 鈥渋nteractome鈥�.