Vitamin D Action

1,25-VD, the bioactive form of vitamin D, was identified as a nutrient a century ago, and is the major regulator of calcium and phosphate homeostasis, responsible for maintenance of bone integrity, and also plays an important role in hair follicle cycling and mammary gland development. The biological effects of 1,25-VD are mainly mediated through the VDR, a member of the nuclear receptor superfamily, which heterodimerizes with the retinoid X receptor (RXR) and binds to response elements located in the promoters of target genes in various tissues, such as bone (osteocalcin, osteopontin, and beta 3 integrin), kidney (24-hydroxylase), and intestine (calbindin).6,7 Like other nuclear receptors, VDR contains an amino-terminal activation function 1 (AF-1) domain, a DNA binding domain (DBD), composed of two hexameric half-sites organized as direct repeats that recognize specific DNA response elements, and a ligand binding domain (LBD) that contains a ligand-regulated transcriptional activation function 2 (AF-2) region.8 Ligand-induced conformational changes in the LBD of VDR create an interface for protein-protein interaction between receptors and a group of intermediate proteins, termed coregulators, that may connect liganded receptors to basal transcription machinery, or that remodel the chromatin structure to facilitate transcription initiation.9

Several coregulators that modulate VDR activity have been identified. Included are positive coregulators such as SRC-1, TIF2/GRIP-1, SRC-3/RAC3/AIB-1, HMG-1/2, TAF(II)55, Smad3, and TRAP220, as well as negative coregulators such as NCoRs, Smad7, and Stat 1.10-18 The VDR-interacting protein (DRIP) complex, identified by affinity column assay, consists of several components, promotes transactivation of VDR in vitro, and demonstrates chromatin remodeling activity.19 Large numbers of coregulators have been identified, and it is believed that they may form several multiprotein complexes to serve particular functions in modulating receptor transactivation. For example, the SWI/SNF complex possesses ATP-dependent chromatin remodeling activity, the CBP and p/CAF complexes possess histone acetyltrans-ferase activity, and the DRIP complex functions to recruit basal transcription factors.20

The phosphorylation status of VDR is also important for modulation of receptor function. For example, phosphorylation of VDR by casein kinase-II promotes its transactivation activity, while phosphorylation of VDR by PKC is thought to negatively regulate its activity. In addition, the tyrosine-phosphorylated VDR exerts increasing affinity for DRIP205, a component of a coregulator complex that acts as a bridge between the basal transcription machinery and VDR.21 A recent report showed that the p38 and JNK-triggered c-Jun/AP-1 pathways transactivate VDR and sensitize breast cancer to vitamin D-induced growth inhibition.22 These lines of evidence indicate that cross-talk between growth factors and VDR-mediated vitamin D action may be involved in modulating vitamin D-mediated growth arrest in cancer cells.

Was this article helpful?

0 0
Hair Loss Prevention

Hair Loss Prevention

The best start to preventing hair loss is understanding the basics of hair what it is, how it grows, what system malfunctions can cause it to stop growing. And this ebook will cover the bases for you. Note that the contents here are not presented from a medical practitioner, and that any and all dietary and medical planning should be made under the guidance of your own medical and health practitioners. This content only presents overviews of hair loss prevention research for educational purposes and does not replace medical advice from a professional physician.

Get My Free Ebook

Post a comment