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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcitriol (1 alpha,25-dihydroxycholecalciferol) inhibits prostate cancer cell growth. It has been shown that inhibition of growth of prostate cancer LNCaP cells by calcitriol is androgen-dependent. Using cDNA microarray we showed that calcitriol induced expression of placental transforming growth factor-beta (PTGF-beta), which is known to suppress cell growth. We studied regulation of PTGF-beta gene expression by calcitriol and 5alpha-dihydrotestosterone and analyzed whether induction of PTGF-beta transcription by calcitriol is androgen-dependent. Using real-time PCR we demonstrate that 5alpha-dihydrotestosterone up-regulates PTGF-beta mRNA. We do not find an effect of 5alpha-dihydrotestosterone or antiandrogen Casodex on calcitriol-induced PTGF-beta mRNA level and conclude that induction of PTGF-beta transcription by calcitriol is androgen-independent.
Mol Biol (Mosk)
PMID:[Transcriptional regulation of placental transforming growth factor-beta by calcitriol in prostate cancer cells is androgen-independent]. 1652 95

It is well known that the efficiency of intestinal active calcium transport is regulated by the Vitamin D receptor pathway and Vitamin D analogs seem to exhibit differential effects on intestinal active calcium transport. To investigate the molecular basis for the difference among Vitamin D analogs, we tested three Vitamin D analogs: 1,25-dihydroxyvitamin D(3), 19-nor-1,25-dihydroxyvitamin D(2), and 1alpha-hydroxyvitamin D(2) ex vivo and in vitro. In 5/6 nephrectomized rat intestinal active calcium transport, 19-nor-1,25-dihydroxyvitamin D(2) did not show a significant effects on intestinal active calcium transport at all the concentrations tested, while 1alpha-hydroxyvitamin D(2) at 0.33 and 0.67 microg/kg and 1,25-dihydroxyvitamin D(3) at 1microg/kg significantly stimulated calcium transport. In Caco-2 cells, 19-nor-1,25-dihydroxyvitamin D(2) did not show a significant effect on calcium transport, while 1,25-dihydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(2) (the active form of 1alpha-hydroxyvitamin D(2)) stimulated calcium transport by 934 and 501% at 0.1microM, respectively. 1,25-Dihydroxyvitamin D(2) potently induced the expression of CALB3 and TRPV6 mRNA with an EC(50) of 0.3 and 1.0nM, whereas 19-nor-1,25-dihydroxyvitamin D(2) was 10-fold less potent than 1,25-dihydroxyvitamin D(2) in inducing CALB3 and TRPV6 mRNA. The three Vitamin D analogs had no significant effect on the expression of PMCA1 mRNA. These Vitamin D analogs did not change the expression of Vitamin D receptor (VDR) up to 10nM, but stimulated CYP24A1 expression in a dose-dependent manner with the potency in the order of 1,25-dihydroxyvitamin D(3)>1,25-dihydroxyvitamin D(2)=19-nor-1,25-dihydroxyvitamin D(2). These results suggest that the differential effect of Vitamin D analogs on stimulating intestinal and Caco-2 calcium transport may be in part due to its different effect on stimulating CALB3 and TRPV6 mRNA expression.
J Steroid Biochem Mol Biol 2007 Jan
PMID:Differential effects of Vitamin D analogs on calcium transport. 1704 42

1,25-Dihydroxyvitamin D(3) and vitamin D(3) analogues, such as EB 1089, potentiate the response to ionizing radiation in breast tumor cells. The current studies address the basis for this interaction by evaluating DNA damage and repair, the effect of interference with reactive oxygen generation, the involvement of p53 and caspase-3, signaling through c-myc, as well as the induction of senescence and multiple modes of cell death. EB 1089 failed to increase the extent of radiation-induced DNA damage or to attenuate the rate of DNA repair. The reactive oxygen scavengers N-acetyl-l-cysteine and reduced glutathione failed to protect the cells from the promotion of cell death by EB 1089 and radiation. Whereas MCF-7 cells expressing caspase-3 showed significant apoptosis with radiation alone as well as with EB 1089 followed by radiation, EB 1089 maintained its ability to confer susceptibility to radiation-induced cell killing, in large part by interference with proliferative recovery. In contrast, in breast tumor cells lacking p53, where radiation promoted extensive apoptosis and the cells failed to recover after radiation treatment, EB 1089 failed to influence the effect of radiation. EB 1089 treatment interfered with radiation-induced suppression of c-myc; however, induction of c-myc did not prevent senescence by radiation alone or radiation-induced cell death promoted by EB 1089. EB 1089 did not increase the extent of micronucleation, indicative of mitotic catastrophe, induced by radiation alone. However, EB 1089 did promote extensive autophagic cell death in the irradiated cells. Taken together, these studies suggest that the effect of EB 1089 treatment on the radiation response is related in part to enhanced promotion of autophagic cell death and in part to interference with the proliferative recovery that occurs with radiation alone in p53 wild-type breast tumor cells.
Mol Cancer Ther 2006 Nov
PMID:Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery. 1712 25

1,25-Dihydroxyvitamin D (1,25D) inhibits growth of prostate cancer cells and has been proposed to play a protective role in prostate cancer. However, 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1), the enzyme responsible for the cellular synthesis of 1,25D, is repressed in prostate cancer cells. Recently, we have identified a role for the transcription factor, Growth Factor Independent-1 (GFI1) in the repression of the CYP27B1 gene in human prostate cancer cell lines. GFI1 is known to form a large protein complex with co-repressors that recruit histone deacetylases. We have proposed a model for the molecular repression of CYP27B1 gene expression. The formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to the silencing of gene expression either by inactivating nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D. These studies demonstrate that GFI1 may play a significant role in the down regulation of endogenous production of 1,25D in prostate cancer cells and could provide a novel insight to future diagnosis and treatment.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Role of oncoprotein growth factor independent-1 (GFI1) in repression of 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1): a comparative analysis in human prostate cancer and kidney cells. 1720 94

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) functions as a systemic signal in vertebrate organisms to control the expression of genes whose products are vital to the maintenance of calcium and phosphorus homeostasis. This regulatory capability is mediated by the vitamin D receptor (VDR) which localizes at DNA sites adjacent to the promoter regions of target genes and initiates the complex events necessary for transcriptional modulation. Recent investigations using chromatin immunoprecipitation techniques combined with various gene scanning methodologies have revealed new insights into the location, structure and function of these regulatory regions. In the studies reported here, we utilized the above techniques to identify key enhancer regions that mediate the actions of vitamin D on the calcium ion channel gene TRPV6, the catabolic bone calcium-mobilizing factor gene RankL and the bone anabolic Wnt signaling pathway co-receptor gene LRP5. We also resolve the mechanism whereby 1,25(OH)(2)D(3) autoregulates the expression of its own receptor. The results identify new features of vitamin D-regulated enhancers, including their locations at gene loci, the structure of the VDR binding sites located within, their modular nature and their functional activity. Our studies suggest that vitamin D enhancers regulate the expression of key target genes by facilitating the recruitment of both the basal transcriptional machinery as well as the protein complexes necessary for altered gene expression.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Perspectives on mechanisms of gene regulation by 1,25-dihydroxyvitamin D3 and its receptor. 1722 45

Calcitriol, the hormonally active form of Vitamin D, inhibits the growth and development of many cancers through multiple mechanisms. Our recent research supports the contributory role of several new and diverse pathways that add to the mechanisms already established as playing a role in the actions of calcitriol to inhibit the development and progression of prostate cancer (PCa). Calcitriol increases the expression of insulin-like growth factor binding protein-3 (IGFBP-3), which plays a critical role in the inhibition of PCa cell growth by increasing the expression of the cell cycle inhibitor p21. Calcitriol inhibits the prostaglandin (PG) pathway by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote carcinogenesis and progression of multiple cancers, the inhibition of the PG pathway may add to the ability of calcitriol to prevent and inhibit PCa development and growth. The combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy. Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of a family of phosphatases that are negative regulators of MAP kinases. Calcitriol induces MKP5 expression in prostate cells leading to the selective dephosphorylation and inactivation of the stress-activated kinase p38. Since p38 activation is pro-carcinogenic and is a mediator of inflammation, this calcitriol action, especially coupled with the inhibition of the PG pathway, contributes to the chemopreventive activity of calcitriol in PCa. Mullerian Inhibiting Substance (MIS) has been evaluated for its inhibitory effects in cancers of the reproductive tissues and is in development as an anti-cancer drug. Calcitriol induces MIS expression in prostate cells revealing yet another mechanism contributing to the anti-cancer activity of calcitriol in PCa. Thus, we conclude that calcitriol regulates myriad pathways that contribute to the potential chemopreventive and therapeutic utility of calcitriol in PCa.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer. 1722 71

In a double blind placebo controlled 3-year osteoporosis study in elderly women, we collected prospective data on falls. The study population comprised 489 normal elderly women aged 65-77 years randomized to four groups: placebo, calcitriol 0.25 mcg b.i.d., conjugated equine estrogens (0.625 mg/day) and calcitriol+estrogen. Falls occurred in 57% of all women. Using a Poisson regression model, the placebo group with low GFR-creatinine clearance (CrCl<60 ml/min) had 60% more falls compared to the group with CrCl> or =60 ml/min. Further sub group analyses showed that there is no increased risk of falls with CrCl 60-70, 70-80 and >90 ml/min. Calcitriol treatment significantly reduced the number of falls by 50% (OR=0.5, 95% CI: 0.4-0.9, p=0.010) compared to placebo in the low CrCl group. The group with lower CrCl had lower calcium absorption (p<0.001), lower serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) (p<0.001) and normal serum 25OHD suggesting that there is decreased conversion of 25OHD to 1,25(OH)(2)D by the aging kidney. It is postulated that the decrease in falls on calcitriol therapy is related to an increase in serum 1,25(OH)(2)D, upregulation of VDR and improvement in muscle strength although one cannot exclude an effect on the central nervous system.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Falls are associated with decreased renal function and insufficient calcitriol production by the kidney. 1723 58

Calcitriol is an antiproliferative prodifferentiating secosteroid that exerts a protective role for some kinds of cancer. Alterations in 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) activity have been found in some tumor cells, but there are no studies performed in human choriocarcinoma. In the present work, calcitriol production and CYP27B1 gene regulation were studied in the human choriocarcinoma cell line JEG-3, and compared with normal human syncytiotrophoblasts (hS) in culture. In JEG-3 cells, secretion of [(3)H]calcitriol was significantly less (P<0.001) than in hS (45+/-17fmol/mg protein versus 174+/-87fmol/mg protein, respectively; n=8). CYP27B1 mRNA was similar in both JEG-3 and hS cells; but the protein was detected only in hS extracts. In contrast to the hS, JEG-3 CYP27B1 gene expression was not regulated by calcitriol or by a cAMP analogue. Our results indicate that in JEG-3 cells calcitriol production is diminished due to CYP27B1 dysregulation and low protein content, and suggest that hyperproliferation could be a consequence of these alterations.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Metabolism of vitamin D in the human choriocarcinoma cell line JEG-3. 1725 77

Calcitriol exerts a diverse range of biological actions including the control of growth and cell differentiation, modulation of hormone secretion, and regulation of reproductive function. The placenta synthesizes calcitriol through the expression of CYP27B1, but little is known about local actions of this hormone in the fetoplacental unit. The objective of this study was to investigate the effects of calcitriol upon progesterone (P(4)) and estradiol (E(2)) secretion in trophoblasts cultured from term human placenta. Cells were incubated in the presence of calcitriol for 18 h and pregnenolone or androstenedione were subsequently added as substrates for the 3beta-hydroxysteroid dehydrogenase (3beta-HSD) or P450-aromatase (CYP19), respectively. Calcitriol stimulated in a dose-dependent manner E(2) and P(4) secretion. The use of a selective inhibitor of PKA prevented the effects of calcitriol upon E(2) secretion, but not on P(4). These results show that calcitriol is a physiological regulator of placental E(2) and P(4) production and suggest a novel role for calcitriol upon placental steroidogenesis.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Estradiol and progesterone synthesis in human placenta is stimulated by calcitriol. 1725 26

1,25-Dihydroxyvitamin D(3) (calcitriol) is the most active natural metabolite of Vitamin D(3). It has strong antiproliferative and differentiating effects on various cell types including breast cancer cells. 25-Hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase, CYP27B1) is one of the key enzymes in the formation of calcitriol. It has been found in breast cancer cells suggesting an autocrine regulation of formation of calcitriol in these cells. Alternative splicing of the encoding genes for this enzyme can possibly play a role in regulating the enzyme level and can explain tissue specific variations of 1alpha-hydroxylase activity. Splice variants containing intron 1 may encode for truncated proteins with deletion of protein domains which are essential for its enzymatic activity. In order to obtain more information on the abundance of 1alpha-hydroxylase splice variants, we performed a highly specific nested touchdown PCR in MCF-7 cells. The full-length sequence of 1alpha-hydroxylase and two different splice variants of this enzyme containing intron 1 were isolated. By Western blot technique we then confirmed the protein products of the full-length enzyme and its splice variants. We hypothesize that that the expression of splice variants can lead to a quantitatively lower expression of the mRNA of the full-length enzyme. The abundance of less active 1alpha-hydroxylase protein variants can alter the local synthesis of calcitriol in the cells and may explain variations of enzymatic activity in different cells and tissues.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Expression of splice variants of 1alpha-hydroxylase in mcf-7 breast cancer cells. 1728 16


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