Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intestinal absorption of dietary calcium is regulated by 1,25-dihydroxycholecalciferol (1,25(OH)(2)D(3)) in humans and in experimental animals but interspecies differences in responsiveness to 1,25(OH)(2)D(3) are found, possibly due to differences in the promoters of genes for intestinal calcium transport proteins or of the Vitamin D receptor (VDR). The epithelial calcium transporter, known as ECAC2 or CAT1, the product of the TRPV6 gene expressed in proximal intestinal enterocytes, is the first step in calcium absorption and studies in mice have shown that its expression is Vitamin D-dependent. In contrast in man, we showed that duodenal TRPV6 mRNA expression was independent of blood 1,25(OH)(2)D(3), although in Caco-2 cells, 1,25(OH)(2)D(3)-dependent changes have been demonstrated. We sought to explain these findings. A consensus Vitamin D response element in the mouse gene is absent in the human gene. We re-analysed our duodenal expression data according to a CDX2-site polymorphism in the VDR promoter. Mean TRPV6 expression was the same, but there was evidence of different responsiveness to 1,25(OH)(2)D(3). In the GG genotype group, but not the AG, duodenal TRPV6 expression increased with 1,25(OH)(2)D(3). We postulate that lower levels of expression of VDR in the GG group produce greater sensitivity to 1,25(OH)(2)D(3).
J Steroid Biochem Mol Biol 2004 May
PMID:Duodenal expression of the epithelial calcium transporter gene TRPV6: is there evidence for Vitamin D-dependence in humans? 1522 92

Calcitriol, the hormonal form of Vitamin D, potentiates the activity of some agents of the anti-cancer immune system including tumor necrosis factor-alpha (TNF-alpha). Different signaling pathways activated by TNF-alpha may be targets for calcitriol action. Activation of p38 MAP kinase was shown to have both pro- and anti-apoptotic actions in TNF-alpha-induced programmed cell death depending on cell context. Treatment of MCF-7 breast cancer cells with TNF-alpha resulted in activation of p38 MAP kinase that persisted for at least 24h. Whereas calcitriol had no effect on the earlier phase of p38 MAP kinase activation (up to 1h), it inhibited the activation of this pathway between one and 24h after exposure to TNF-alpha. Both calcitriol and the p38 MAP kinase inhibitor SB203580 enhanced TNF-alpha-induced cytotoxicity and drop in mitochondrial membrane potential, but their combined effect was sub-additive. Taken together, these findings suggest that p38 MAP kinase plays an anti-apoptotic role in TNF-alpha-induced cytotoxicity in MCF-7 cells and that the synergistic interaction between TNF-alpha and calcitriol, leading to mitochondrial damage and subsequent cell death, is partially due to modulation of this signaling pathway.
J Steroid Biochem Mol Biol 2004 May
PMID:The role of p38 MAP kinase in the synergistic cytotoxic action of calcitriol and TNF-alpha in human breast cancer cells. 1522 1

Cellular calcium has been implicated in induction of apoptosis. We have shown that 1,25(OH)(2)D(3)-induced apoptosis is associated with a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) resulting from depletion of the endoplasmic reticulum (ER) Ca(2+) stores and activation of the voltage-insensitive Ca(2+) entry pathway [1,25-Dihydroxyvitamin D(3), intracellular Ca(2+) and apoptosis in breast cancer cells, in: A.W. Norman, R. Bouillon, M. Thomasset (Eds.), Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid Hormone, University of California, Riverside, 1997, pp. 473-474; Vitamin D and intracellular calcium, in: P. Quinn, V. Kagan (Eds.), Subcellular Biochemistry: Fat-Soluble Vitamins, Plenum Press, New York, 1998, pp. 271-297; 1,25-Dihydroxyvitamin D(3) and calcium signaling, in: A.W. Norman, R. Bouillon, M. Thomasset (Eds.), Vitamin D Endocrine System: Structural, Biological, Genetic and Clinical Aspects, University of California, Riverside, 2000, pp. 715-718; 1,25-Dihydroxyvitamin D(3) triggers calcium-mediated apoptosis in breast cancer cells, in: A.W. Norman, R. Bouillon, M. Thomasset (Eds.), Vitamin D Endocrine System: Structural, Biological, Genetic and Clinical Aspects, University of California, Riverside, 2000, pp. 399-402; Endocrine 9 (1998) 321]. This study was undertaken to investigate mechanism of 1,25(OH)(2)D(3)-induced apoptosis in breast cancer cells and compare effects of the hormone on Ca(2+) and apoptosis in cancer and normal human mammary epithelial cells. The treatment of MCF-7 breast cancer cells with 1,25(OH)(2)D(3) induced a sustained increase in [Ca(2+)](i) and activated the Ca(2+)-dependent proapoptotic proteases, micro-calpain and caspase-12, as evaluated with antibodies to active (cleaved) forms of the enzymes and the calpain substrate. The selective inhibition of Ca(2+) binding sites of micro-calpain decreased apoptotic indices in the 1,25(OH)(2)D(3)-treated cells. 1,25(OH)(2)D(3) did not induce apoptosis in normal human mammary epithelial cells (HMECs), as evaluated by DNA fragmentation (TUNEL), loss of the plasma membrane asymmetry (Annexin V assay) and morphological criteria. In these cells, 1,25(OH)(2)D(3) triggered a transient Ca(2+) response, which was not accompanied by the calpain and caspase activation. HMEC, but not MCF-7 cells expressed the Ca(2+) binding protein calbindin-D(28k) and buffered Ca(2+) increases induced by a Ca(2+) ionophore ionomycin. In conclusion, we have identified the novel apoptotic pathway in breast carcinoma cells treated with 1,25(OH)(2)D(3): increase in [Ca(2+)](i) -->micro-calpain activation --> caspase-12 activation --> apoptosis. Our findings also imply that differences of Ca(2+) regulatory mechanisms in breast cancer versus normal mammary epithelial cells underlay resistance of normal cells and susceptibility of cancer cells to 1,25(OH)(2)D(3)-induced Ca(2+)-mediated apoptosis.
J Steroid Biochem Mol Biol 2004 May
PMID:Calcium as a mediator of 1,25-dihydroxyvitamin D3-induced apoptosis. 1522 13

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2) D(3)) is a potent regulator of cell growth and differentiation, with recent evidence showing inhibition of tumor invasion, angiogenesis and tumor cell death. The growth-inhibitory properties of 1,25-(OH)(2) D(3) could be harnessed in the treatment of patients with cancer if the development of systemic hypercalcemia is avoided. Hepatocellular cancer (HCC) presents a setting where the tumor is accessible for treatment through the hepatic artery and also where the tumor is highly lipiodol avid. On this basis, we hypothesised that, 1,25-(OH)(2) D(3) dissolved in lipiodol and administered through the hepatic artery may prove to be a rational approach to the use of the drug in the treatment of HCCs. In brief, 6 years of work with 1,25-(OH)(2) D(3) at cellular, animal and clinical level has provided us with plenty of support for this hypothesis. Sensitivity of HCCs in cell culture to 1,25-(OH)(2) D(3), growth retardation of human HCC xenografts in nude mice, uptake and retention of 1,25-(OH)(2) D(3)-lipiodol by liver tumors in cell culture and animals, escalation of the 1,25-(OH)(2) D(3) dose by 100x without the development of hypercalcemia in both liver tumor bearing rats and in patients with HCC are some of the evidence that will be discussed in this paper.
J Steroid Biochem Mol Biol 2004 May
PMID:1,25-Dihydroxyvitamin D3 in lipiodol for the treatment of hepatocellular carcinoma: cellular, animal and clinical studies. 1522 30

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.
J Steroid Biochem Mol Biol 2004 May
PMID:Anti-tumor activity of calcitriol: pre-clinical and clinical studies. 1522 31

UVB irradiation of cultured human keratinocytes induces both the conversion of 7-dehydrocholesterol (7-DHC) to calcitriol (1alpha,25(OH)(2)D(3)) and the release of tumor necrosis factor-alpha (TNF-alpha) in these cells. Calcitriol synthesis in human keratinocytes was reduced in the presence if a neutralizing polyclonal antibody directed against human TNF-alpha. On the other hand, we found a 1.7-fold higher stimulatory effect of UVB on liberation of TNF-alpha in cultured keratinocytes enriched with 7-DHC compared with irradiated cell cultures in absence of 7-DHC. These observations argue in favor of a synergetic relationship between generation of TNF-alpha and calcitriol in UVB irradiated keratinocytes. In addition, we found that TNF-alpha potently increases the conversion rate of Vitamin D(3) (cholecalciferol) to calcitriol in this cell system. The UVB-triggered formation of both TNF-alpha and calcitriol in cultured keratinocytes was wavelength-, time- and dose-dependent. Maximum formation of TNF-alpha and calcitriol was found at 300 nm and UVB doses of 30 mJ/cm2. The enhancement of both the formation of TNF-alpha and calcitriol in keratinocytes by UVB may be of relevance for regulation of growth and apoptosis in light-exposed epidermal cells and, in addition, may play a role in the UVB treatment of diseased skin including psoriasis.
J Steroid Biochem Mol Biol 2004 May
PMID:Role for tumor necrosis factor-alpha in UVB-induced conversion of 7-dehydrocholesterol to 1alpha,25-dihydroxyvitamin D3 in cultured keratinocytes. 1522 39

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is anti-apoptotic in human keratinocytes, melanocytes and fibroblasts after ultraviolet (UV)-exposure. To date, there is no published data on the effects of 1,25(OH)(2)D(3) or its analogs on DNA damage in irradiated skin cells. In these skin cells, 24h pre-treatment with 1,25(OH)(2)D(3) dose-dependently (10(-12) to 10(-8)M) decreased CPD damage by up to 60%. This photoprotective effect was also seen if the 1,25(OH)(2)D(3) was added immediately after irradiation and was mimicked by QW-1624F2-2 (QW), a low-calcemic 1beta-hydroxymethyl-3-epi-16-ene-24,24-difluoro-26,27-bis homo hybrid analog. The well-studied low calcemic, rapid acting agonist analogs 1alpha,25(OH)(2)lumisterol(3) (JN) and 1alpha,25(OH)(2)-7-dehydrocholesterol (JM) also protected skin cells from UV-induced cell loss and CPD damage to an extent comparable with that of 1,25(OH)(2)D(3). In contrast, the rapid response antagonist analog 1beta,25(OH)(2)D(3) (HL) completely abolished the photoprotective effects (reduced cell loss and reduced CPD damage) produced by treatment with 1,25(OH)(2)D(3), JN, JM and QW. Evidence for involvement of the nitric oxide pathway in the protection from CPD damage by 1,25(OH)(2)D(3) was obtained. These data provide further evidence for a role of the vitamin D pathway in the intrinsic skin defenses against UV damage. The data also support the hypothesis that the photoprotective effects of 1,25(OH)(2)D(3) are mediated via the rapid response pathway(s).
J Steroid Biochem Mol Biol 2004 May
PMID:1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway. 1522 40

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] exerts anti-proliferative, differentiating and apoptotic effects on prostatic cells. These activities, in addition to epidemiologic findings that link Vitamin D to prostate cancer risk, support the use of 1,25(OH)(2)D(3) for prevention or therapy of prostate cancer. The molecular mechanisms by which 1,25(OH)(2)D(3) exerts antitumor effects on prostatic cells are not well-defined. In addition, there is heterogeneity among the responses of various prostate cell lines and primary cultures to 1,25(OH)(2)D(3) with regard to growth inhibition, differentiation and apoptosis. To understand the basis of these differential responses and to develop a better model of Vitamin D action in the prostate, we performed cDNA microarray analyses of primary cultures of normal and malignant human prostatic epithelial cells, treated with 50 nM of 1,25(OH)(2)D(3) for 6 and 24 h. CYP24 (25-hydroxyvitamin D(3)-24-hydroxylase) was the most highly upregulated gene. Significant and early upregulation of dual specificity phosphatase 10 (DUSP10), validated in five additional primary cultures, points to inhibition of members of the mitogen-activated protein kinase (MAPK) superfamily as a key event mediating activity of 1,25(OH)(2)D(3) in prostatic epithelial cells. The functions of other regulated genes suggest protection by 1,25(OH)(2)D(3) from oxidative stress. Overall, these results provide new insights into the molecular basis of antitumor activities of Vitamin D in prostate cells.
J Steroid Biochem Mol Biol 2004 Oct
PMID:Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. 1555 7

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] induces the synthesis of 25-hydroxyvitamin D(3) 24-hydroxylase [24(OH)ase], an enzyme involved in its catabolism, thereby regulating its own metabolism. Here we demonstrate that CCAAT enhancer binding protein beta (C/EBPbeta) is induced by 1,25(OH)(2)D(3) in kidney and in osteoblastic cells and is a potent enhancer of vitamin D receptor (VDR)-mediated 24(OH)ase transcription. Transfection studies indicate that 1,25(OH)(2)D(3) induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBPbeta. Suppression of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBPbeta(-/-) mice. A C/EBP site was identified at positions -395 to -388 (-395/-388) in the rat 24(OH)ase promoter. Mutation of this site inhibited C/EBPbeta binding and markedly attenuated the transcriptional response to C/EBPbeta. We also report the cooperation of CBP/p300 with C/EBPbeta in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH)(2)D(3) but also parathyroid hormone (PTH) can induce C/EBPbeta expression in osteoblastic cells. PTH potentiated the induction of C/EBPbeta and 24(OH)ase expression in response to 1,25(OH)(2)D(3) in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBPbeta in the protein kinase A-mediated induction of VDR transcription. From this study a fundamental role has been established for the first time for cooperative effects and cross talk between the C/EBP family of transcription factors and VDR in 1,25(OH)(2)D(3)-induced transcription. These findings also indicate a novel role for C/EBPbeta in the cross talk between PTH and 1,25(OH)(2)D(3) that involves the regulation of VDR transcription.
Mol Cell Biol 2005 Jan
PMID:Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D3 24-hydroxylase. 1560 67

A number of hormonal ligands and/or the nuclear receptors that mediate their actions have been targeted for prostate cancer therapy. Androgens, the ligands for the androgen receptor (AR), are critical for the growth of prostate cancer. Inhibition of androgen production has been the mainstay of treatment for advanced prostate cancer for decades. Other more recently tested targets include retinoid receptors (RAR and RXR), glucocorticoid receptors (GR), estrogen receptors (ER) and peroxisome proliferator-activated receptors (PPAR). Calcitriol, acting through the Vitamin D receptor (VDR), has many tumor suppressive activities in the prostate, including inhibition of proliferation, induction of apoptosis and/or differentiation, and reduction of cellular invasion. Because of these properties, calcitriol and its less hypercalcemic analogs are being evaluated as agents to prevent or treat prostate cancer. Androgens, retinoids, glucocorticoids, estrogens and agonists of PPAR directly or indirectly impact Vitamin D signaling pathways, and vice versa. In order to design the most effective strategies to use calcitriol to prevent or treat prostate cancer, the interactions of other nuclear receptors and their ligands with the Vitamin D signaling pathway need to be considered.
J Steroid Biochem Mol Biol 2004 Nov
PMID:Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer. 1566 94


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