Vitamin D signaling is dependent on the availability and turnover of the active Vitamin D receptor (VDR) ligand 1,25-dihydroxycholecalciferol and on the efficiency of VDR transactivation. Activating and inactivating secosteroid metabolizing p450 enzymes, e.g. 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase, are responsible for ligand availability on the basis of substrate production in the skin and of nutritional intake of precursors. Net availability of active hormone depends on the delivery of substrate and the balance of activating and inactivating enzymes. 1Alpha-hydroxylase is the critical activating enzyme. It is expressed in the kidney for systemic supply and in target tissues for local secosteroid activation. It is upregulated in the kidney by low calcium intake and parathyroid hormone, downregulated by phosphatonins and proinflammatory signal transduction. Transactivation of VDR depends on the correct molecule structure, effective nuclear translocation and the presence of the unliganded heterodimer partner retinoid X-receptor (RXR) and other nuclear cofactors. Rapid Vitamin D-dependent membrane associated effects and consecutive second messenger activation exert an own pattern of gene regulation. A membrane receptor for these effects is hypothesized but not yet identified. Rickets is the long known clinical syndrome of impaired Vitamin D signaling due to Vitamin D3 deficiency. It can be caused by inherited defects of the cascade, nutritional deficits, lack of sunlight exposure, malabsorption and underlying diseases like chronic inflammation. It has been shown during the last decades that many modifiers of Vitamin D signaling are targets of disease in terms of inherited and acquired syndromes and that Vitamin D signaling is modulated at multiple levels and is more complex than mere mechanistic ligand/receptor/DNA interaction.
"To a lesser extent, vitamin D can be sourced in the diet from foods such as fortified dairy products and cereals, oily fish and fish liver oils . Synthesized or dietary vitamin D, from the skin and the gut, respectively, are hydroxylated in the liver to form 25-hydroxyvitamin D [25-OHD] through the action of cytochrome P450 enzymes), which is converted to the biologically active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], in the kidney and other tissues by the 1a-hydroxylase . The concentration of 25-hydroxyvitamin D in blood is regarded as the best indicator of vitamin D status, because it is quantitatively related to the supply of vitamin D over the weeks preceding blood sample collection. "
[Show abstract][Hide abstract] ABSTRACT: Evidence is increasing that suggests an expanded role of vitamin D in health outcomes apart from its classic actions on the bone and calcium homeostasis. Vitamin D deficiency has been associated with some chronic respiratory illnesses; one of them is chronic obstructive pulmonary disease (COPD).
"Such changes in gene expression are significant in terms of modulation of cell behaviour. 24-Hydroxylase is a key enzyme in the catabolic pathway of vitamin D 3 metabolism, the promoter of which contains a classical VDRE and is induced by the VDR in almost every tissue examined . Potentiation by BAG-1L of vitamin-D-dependent 24-hydroxylase promoter activity suggests that not only is Bag-1L involved in enhancing Fig. 9 – BAG-1L enhances transactivation of 1α,25(OH) 2 D 3 -responsive gene promoters. "
[Show abstract][Hide abstract] ABSTRACT: In oral cancers, cytoplasmic BAG-1 overexpression is a marker of poor prognosis. BAG-1 regulates cellular growth, differentiation and survival through interactions with diverse proteins, including the vitamin D receptor (VDR), a key regulator of keratinocyte growth and differentiation. BAG-1 is expressed ubiquitously in human cells as three major isoforms of 50 kDa (BAG-1L), 46 kDa (BAG-1M) and 36 kDa (BAG-1S) from a single mRNA. In oral keratinocytes BAG-1L, but not BAG-1M and BAG-1S, enhanced VDR transactivation in response to 1α,25-dihydroxyvitamin D 3. BAG-1L was nucleoplasmic and nucleolar, whereas BAG-1S and BAG-1M were cytoplasmic and nucleoplasmic in localisation. Having identified the nucleolar localisation sequence in BAG-1L, we showed that mutation of this sequence did not prevent BAG-1L from potentiating VDR activity. BAG-1L also potentiated transactivation of known vitamin-D-responsive gene promoters, osteocalcin and 24-hydroxylase, and enhanced VDR-dependent transcription and protein expression of the keratinocyte differentiation marker, involucrin. These results demonstrate endogenous gene regulation by BAG-1L by potentiating nuclear hormone receptor function and suggest a role for BAG-1L in 24-hydroxylase regulation of vitamin D metabolism and the cellular response of oral keratinocytes to 1α,25-dihydroxyvitamin D 3 . By contrast to the cytoplasmic BAG-1 isoforms, BAG-1L may act to suppress tumorigenesis. (A. Hague). Abbreviations: NR, nuclear receptor; GR, glucocorticoid receptor; AR, androgen receptor; ER, oestrogen receptor; RAR, retinoic acid receptor; VDR, vitamin D receptor; NK, primary normal oral keratinocytes; 1α,25(OH) 2 D 3 , 1α,25-dihydroxyvitamin D 3 ; VDRE, vitamin D response element; K-sfm, keratinocyte serum-free medium; FBS, foetal bovine serum; EGF, epidermal growth factor; PBS, phosphate buffered saline; IRES, internal ribosomal entry site; Å, Angstrom; PCNA, proliferating cell nuclear antigen 0014-4827/$ – see front matter a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m w w w. e l s e v i e r. c o m / l o c a t e / y e x c r
"NRs are involved in a diverse range of regulatory functions, such as in development, cellular growth, inflammation and metabolism (El-Sankary et al., 2001, 2002; Phillips et al., 2003; Aouabdi et al., 2006; Carlberg and Dunlop, 2006; Ebert et al., 2006; Cutress et al., 2008). NRs work as transcription factors, the activity of which is regulated by intra- and extracellular signaling molecules. "
[Show abstract][Hide abstract] ABSTRACT: Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be required for therapies to become effective across mankind. On the other hand, diverse combinations of internal and external perturbation factors may cause a similar shift in network functioning. We offer this as an explanation for the multi-factorial nature of most diseases: they are ‘systems biology diseases’, or ‘network diseases’. Here we focus on neurodegenerative diseases, like Parkinson’s disease, as an example. Because of the inherent complexity of these networks, it is difficult to understand multi-factorial diseases using simply our ‘naked brain’. When describing interactions between biomolecules through mathematical equations and integrating those equations into a mathematical model, we try to reconstruct the emergent properties of the system in silico. The reconstruction of emergence from interactions between huge numbers of macromolecules is one of the aims of systems biology. Systems biology approaches enable us to break through the limitation of the human brain to perceive the extraordinarily large number of interactions, but this also means that we delegate the understanding of reality to the computer. We no longer recognize all those essences in the system’s design crucial for important physiological behavior (the so-called ‘design principles’ of the system). In this paper we review evidence that by using more abstract approaches and by experimenting in silico, one may still be able to discover and understand the design principles that govern behavioral emergence.
Frontiers in Physiology 07/2012; 3:291. DOI:10.3389/fphys.2012.00291 · 3.53 Impact Factor
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