Vitamin D Sterol/VDR Conformational Dynamics and Nongenomic Actions

Mizwicki, Mathew T.; Norman, Anthony W.

doi:10.1016/b978-0-12-381978-9.10015-0

Cited by 12 publications

(6 citation statements)

References 180 publications

(234 reference statements)

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“…The mechanism, whereby immediate signal events are provoked, is still not entirely clear [ 20 ] as a number of mechanisms have been proposed to explain this phenomenon. One hypothesis is that a small portion of classical VDR is localized at the plasma membrane and 1,25D binds to an alternative ligand binding pocket to activate signal transduction from the cell membrane [ 21 ]. An alternative viewpoint is the existence of a membrane receptor for 1,25D that is distinct from VDR and is responsible for the rapid actions of 1,25D.…”

Section: 1α25-dihydroxyvitamin D 3 -Driven Celmentioning

confidence: 99%

The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

Marcinkowska

Wallace

Brown

2016

IJMS

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The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D3 (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues.

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Section: 1α25-dihydroxyvitamin D 3 -Driven Celmentioning

confidence: 99%

The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

Marcinkowska

Wallace

Brown

2016

IJMS

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“…The most important and the best documented is the so-called “genomic pathway,” with its most important player a vitamin D receptor (VDR). The less well described is “nongenomic pathway,” which consists of intracellular signalling molecules, such as mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K), and others, activated by mechanisms that are not fully understood now [ 6 ]. It is believed that both pathways need to be activated for full biological activity of 1,25(OH) 2 D and that the most probable mediator of these actions is a putative membrane VDR (mVDR) [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability

Gocek

Baurska

Marchwicka

et al. 2012

Leukemia Research and Treatment

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1α,25-Dihydroxyvitamin D3(1,25(OH)2D) exerts its biological activities through vitamin D receptor (VDR), which is a member of the superfamily of steroid receptors, that act as ligand-dependent transcription factors. Ligated VDR in complex with retinoid X receptor (RXR) binds to regulatory regions of 1,25(OH)2D-target genes. 1,25(OH)2D is able to induce differentiation of leukemic blasts towards macrophage-like cells. Many different acute myeloid leukemia (AML) cell lines respond to 1,25(OH)2D by increasing CD14 cell surface receptor, some additionally upregulate CD11b and CD11c integrins. In untreated AML cells VDR protein is present in cytosol at a very low level, even though its mRNA is continuously expressed. Ligation of VDR causes protein stabilization and translocation to the cell nuclei, where it regulates transcription of target genes. Several important groups of genes are regulated by 1,25(OH)2D in HL60 cells. These genes include differentiation-related genes involved in macrophage function, as well as a gene regulating degradation of 1,25(OH)2D, namely CYP24A1. We summarize here the data which demonstrate that though some cellular responses to 1,25(OH)2D in AML cells are transcription-dependent, there are many others which depend on intracellular signal transduction, protein trafficking and stabilization. The final effect of 1,25(OH)2D action in leukemic cells requires all these acting together.

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“…The complex includes histone acetylase which relaxes chromatin structure to make DNA accessible for RNA polymerase and to initiate transcription of target genes (6). The less precisely described is 'non-genomic pathway' which consists of intracellular signalling molecules, such as mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K) and others activated by a putative membrane VDR (mVDR) (7).…”

Section: Introductionmentioning

confidence: 99%

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

et al. 2012

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1,25-Dihydroxyvitamin D3 (1,25D) is implicated in many cellular functions including cell proliferation and differentiation, thus, exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D are its potent calcemic and phosphatemic activities. Therefore, synthetic analogs of 1,25D for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. Previously, we described pro-differentiating effects of vitamin D2 analogs with extended and branched side-chains. Analogs with side-chains extended by a pair of one (PRI-1906) or two carbon units (PRI-1907) displayed elevated cell-differentiating activity towards some acute leukemia cell lines (AML) in comparison to 1,25D. In this study, the potential mechanism of this superagonistic activity of the analogs was addressed. At first, possible differences in the expression of CYP24A1, a major catabolizing enzyme for vitamin D compounds and resulting differences in the degradation of analogs were investigated. In addition, interactions of the analogs with vitamin D receptor (VDR) and resulting activation of CCAAT-enhancer-binding protein β (C/EBPβ) were studied. The results obtained show that superagonistic pro-differentiating activities of analogs PRI-1906 and PRI-1907 do not seem to be caused by their altered catabolism, but most probably by altered interactions with VDR and resulting downstream proteins.

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Vitamin D Sterol/VDR Conformational Dynamics and Nongenomic Actions

Cited by 12 publications

References 180 publications

The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

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