Mark Robert Haussler

The University of Arizona College of Medicine-Phoenix · Basic Medical Sciences

The hormonal vitamin D metabolite, 1,25‐dihydroxyvitamin D (1,25D), produced in kidney, acts in numerous end‐organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand‐controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target...

Mediated by the nuclear vitamin D receptor (VDR), the hormonally active vitamin D metabolite, 1,25-dihydrox-yvitamin D 3 (1,25D), is known to regulate expression of genes impacting calcium and phosphorus metabolism, the immune system, and behavior. Urolithin A, a nutrient metabolite derived from pomegranate, possibly acting through AMP kinase (AMPK...

The active vitamin D hormone, 1,25‐dihydroxyvitamin D (1,25D), mediates its biological effects by binding to the nuclear vitamin D receptor (VDR) and promoting heterodimerization with retinoid X receptors (RXRs). Various nutraceuticals, including resveratrol and curcumin, have been postulated to interact with the vitamin D signaling pathway. More r...

Recent studies suggest that the biologically active form of vitamin D, 1,25‐dihydroxyvitamin D (1,25D), plays a role in potentially delaying the aging process, functions as an anti‐carcinogenic agent, and also prevents oxidative damage. 1,25D binding to the vitamin D receptor (VDR) promotes heterodimerization of VDR with the retinoid X receptor (RX...

Background Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5-HT; serotonin) and 1,25-dihydroxyvitamin D3 (1,25D; active vitamin D metabolite), are proposed to play a role in the atypical social behaviors associated with psychological conditions including autism spectrum disorders and depression. We reported previously that 1,25D...

The Klotho gene has been closely associated with delayed onset of aging. Inhibition of the klotho protein promotes aging‐like phenotypes, while its overexpression has been found to extend lifespan in mice. The single‐pass transmembrane isoform of klotho (m‐klotho) forms a receptor complex with the fibroblast growth factor (FGF) receptor to create a...

The active form of vitamin D ³ , 1,25‐dihydroxyvitamin D (1,25D), and serotonin (5‐HT) are postulated to play significant roles in abnormal social behavior associated with psychological conditions including autism spectrum disorders (ASDs) and depression. Moreover, we have observed that 1,25D regulates synthesis of two isoforms of tryptophan hydrox...

Treatment with 1,25-dihydroxyvitamin D₃ (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (LCE)3 genes involved in skin repair. In psoriasis patients, the majority of whom harbor genomic deletion of LCE3B and LCE3C (LCE3C_LCE3B-del), we propose that certain dietary analogues of 1,25D activate the ex...

The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitat...

1,25-Dihydroxyvitamin D3 (1,25D) is the endocrine metabolite of vitamin D that signals through binding to the vitamin D receptor (VDR). The ligand–receptor complex transcriptionally regulates genes that encode factors promoting intestinal calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related...

While hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in both bile acid metabolism and in the development of colorectal neoplasia. Employing a cross-sectional...

The two compounds, 1,25‐dihydroxyvitamin D (1,25D, vitamin D) and 5‐hydroxytryptamine (5‐HT, serotonin), have been proposed to play a significant role in abnormal social behavior associated with psychological conditions including autism spectrum disorders (ASDs) and depression; however, the mechanism underlying these associations has yet to be eluc...

The human klotho gene encodes a protein that can generate two isoforms: a single‐pass transmembrane protein (mKlotho) or a secreted peptide (sKlotho) formed from the cleavage of the former. The two isoforms likely possess physiologically unique roles, as mKlotho is known to serve as a membrane‐bound coreceptor for FGF23, while sKlotho may function...

1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related osteopor...

In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor-23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression, whil...

To investigate vitamin D-related control of brain-expressed genes, candidate vitamin D responsive elements (VDREs) at -7/-10 kb in human tryptophan hydroxylase (TPH)2 were probed. Both VDREs bound the vitamin D receptor (VDR)-retinoid X receptor (RXR) complex and drove reporter gene transcription in response to 1,25-dihydroxyvitamin D3 (1,25D). Bra...

The 1,25-dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle. We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (V...

The PSORS4 genetic risk factor for psoriasis is a deletion of two late cornified envelope (LCE) genes (LCE3C_LCE3Bdel) in a cluster of five LCE3 genes with a proposed role in skin repair. We previously showed that 1,25-dihydroxyvitamin D3 (1,25D) modestly upregulates transcripts from all five LCE3 genes as monitored by real time PCR in primary huma...

The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine if their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA...

Psoriasis is a chronic inflammatory skin disease featuring abnormal keratinocyte proliferation and differentiation. A genetic risk factor for psoriasis (PSORS4) is a deletion of LCE3B and LCE3C genes encoding structural proteins in terminally differentiated keratinocytes. Because analogs of 1,25-dihydroxyvitamin D3 (1,25D) are used in psoriasis tre...

Vitamin D is a well-studied agent for cancer chemoprevention and treatment. Its chief circulating metabolite, 25-hydroxyvitamin D, is converted into the active hormone 1,25-dihydroxyvitamin D (1,25D) by the cytochrome P450 enzyme CYP27B1 in kidney and other tissues. 1,25D is then deactivated by CYP24A1 and ultimately catabolized. Colorectal carcino...

Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption and to prevent hypervitaminosis D by feedback repressing 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is induced by the nuclear vitamin...

1.1 Vitamin D Bioactivation and Its Endocrine/ Mineral Feedback Control...................................3 1.2 Biological Responses to the 1,25D Hormone Are Widespread.................................................5 1.3 Structure–Function of VDR and Mechanisms of Gene Regulation..........................................7 1.4 VDR Binds Nonvitamin...

The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recr...

Isoforms of the mammalian klotho protein serve as membrane co-receptors that regulate renal phosphate and calcium reabsorption. Phosphaturic effects of klotho are mediated in cooperation with fibroblast growth factor receptor-1 and its FGF23 ligand. The vitamin D receptor and its 1,25-dihydroxyvitamin D(3) ligand are also crucial for calcium and ph...

1,25-dihydroxyvitamin D (1,25D), through association with the nuclear vitamin D receptor (VDR), exerts control over a novel endocrine axis consisting of the bone-derived hormone FGF23, and the kidney-expressed klotho, CYP27B1, and CYP24A1 genes, which together prevent hyperphosphatemia/ectopic calcification and govern the levels of 1,25D to maintai...

The conformationally flexible secosteroid, 1α,25(OH)₂vitamin D₃ (1α,25(OH)₂D₃) initiates biological responses via binding to the vitamin D receptor (VDR). The VDR contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative pocket (VDR-AP), that respectively bind a bowl-like ligand configuration (gene transcription) o...

Small Angle X-ray Scattering and Fluorescence Resonance Energy Transfer techniques have determined the structure of the hypocalcemic vitamin-D-resistant rickets (hVDR) DNA-binding domain (DBD) and ligand-binding domain (LBD) together in the full-length receptor, heterodimerized with full-length RXR α, docked on a VDRE, and occupied with 1,25(OH)2D3...

The mammalian hair cycle requires both the vitamin D receptor (VDR) and the hairless (Hr) corepressor, each of which is expressed in the hair follicle. Hr interacts directly with VDR to repress VDR-targeted transcription. Herein, we further map the VDR-interaction domain to regions in the C-terminal half of Hr that contain two LXXLL-like pairs of m...

The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression...

The nuclear vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D(3) (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate (LCA), was recognized as a novel VDR ligand. Using reporter gene and mammalian two-hybrid systems, immunoblotting, competitive ligand displacement and quantitative real-time...

The activity of beta-catenin, commonly dysregulated in human colon cancers, is inhibited by the vitamin D receptor (VDR), and this mechanism is postulated to explain the putative anti-cancer activity of vitamin D metabolites in the colon. We investigated the effect of a common FokI restriction site polymorphism (F/f) in the human VDR gene as well a...

The human vitamin D receptor (VDR) is a key nuclear receptor that binds nutritionally derived ligands and exerts bioeffects that contribute to bone mineral homeostasis, detoxification of exogenous and endogenous compounds, cancer prevention, and mammalian hair cycling. Liganded VDR modulates gene expression via heterodimerization with the retinoid...

The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also contro...

1,25-Dihydroxyvitamin D(3) (1,25D) is known primarily as a regulator of calcium, but 1,25D also promotes phosphate absorption from intestine, reabsorption from kidney, and bone mineral resorption. FGF23 is a newly discovered phosphaturic hormone that, like PTH, lowers serum phosphate by inhibiting renal reabsorption via Npt2a. We show that 1,25D st...

The proposed mode of action of 1,25 (OH)2D3 is reviewed by describing the following aspects of this hormone: the in vivo localization of labeled 1,25 (OH)2D3 within the target intestine; the isolation and characterization of the cytoplasmic receptor for 1,25 (OH)2D3 from chick intestine; the discovery of new target sites for 1,25 (OH)2D3, possibly...

Fibroblast growth factor (FGF)23 is a phosphaturic hormone that decreases circulating 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and elicits hypophosphatemia, both of which contribute to rickets/osteomalacia. It has been shown recently that serum FGF23 increases after treatment with renal 1,25(OH)(2)D(3) hormone, suggesting that 1,25(OH)(2)D...

The relationship of vitamin D with colorectal and other cancers is a rapidly expanding field of study. The pathway through which vitamin D exerts transcriptional effects is complex and involves the action of other nutrients. Recent epidemiologic work underscores the importance of considering the

The vitamin D receptor (VDR) binds to and mediates the effects of the 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) hormone to alter gene transcription. A newly recognized VDR ligand is the carcinogenic bile acid, lithocholic acid (LCA). We demonstrate that, in HT-29 colon cancer cells, both LCA and 1,25(OH)(2)D(3) induce expression of cytochrome P4...

The human vitamin D receptor (hVDR), which is a substrate for several protein kinases, mediates the actions of its 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) ligand to regulate gene expression. To determine the site, and functional impact, of cAMP-dependent protein kinase (PKA)-catalyzed phosphorylation of hVDR, we generated a series of C-terminally tr...

The PHEX gene encodes an endopeptidase expressed in osteoblasts that inactivates an uncharacterized peptide hormone, phosphatonin, which suppresses bone mineralization as well as renal phosphate reabsorption and vitamin D bioactivation. We demonstrate that 1α-25-dihydroxyvitamin D (1,25(OH)2D3), the, active renal vitamin D metabolite, decreases PHE...

Nuclear hormone receptor-responsive element binding specificity has been reported to reside predominantly in the proximal box (P-box), three amino acids located in a DNA-recognition alpha-helix situated on the C-terminal side of the first zinc finger. To further define the residues in the vitamin D receptor (VDR) DNA binding domain (DBD) that media...

Both the vitamin D receptor (VDR) and hairless (hr) genes play a role in the mammalian hair cycle, as inactivating mutations in either result in total alopecia. VDR is a nuclear receptor that functions as a ligand-activated transcription factor, whereas the hairless gene product (Hr) acts as a corepressor of both the thyroid hormone receptor (TR) a...

The nuclear vitamin D receptor (VDR) mediates the actions of its 1,25-dihydroxyvitamin D(3) ligand to control gene expression in terrestrial vertebrates. Prominent functions of VDR-regulated genes are to promote intestinal absorption of calcium and phosphate for bone mineralization and to potentiate the hair cycle in mammals. We report the cloning...

The nuclear vitamin D receptor (VDR) mediates the effects of 1,25-dihydroxyvitamin D(3) (1,25D(3)) to alter intestinal gene transcription and promote calcium absorption. Because 1,25D(3) also exerts anti-cancer effects, we examined the efficacy of 1,25D(3) to induce cytochrome P450 (CYP) enzymes. Exposure of human colorectal adenocarcinoma cells (H...

The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,25-dihydroxyvitamin D3[1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are o...

Vitamin D is bioactivated in kidney to its hormonal form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), functioning to prevent rickets/osteomalacia by stimulating small intestinal calcium absorption. Plasma 1,25(OH)2D3 is depressed in patients with chronic renal failure and elevated in subjects with calcium urolithiasis, but normal in osteoporosis. The c...

Two controversial aspects in the mechanism of human vitamin D receptor (hVDR) action are the possible significance of VDR homodimers and the functional role of receptor phosphorylation. To address these issues, milligram quantities of baculovirus-expressed hVDR were purified to 97% homogeneity, and then tested for binding to the rat osteocalcin vit...

The vitamin D receptor (VDR) stimulates transcription as a 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-activated heterodimer with retinoid X receptor (RXR). RXR also forms homodimers to mediate 9-cis retinoic acid (9-cis RA)-induced gene expression. Both receptors possess a C-terminal hormone-dependent activation function-2 (AF-2), a highly conser...

The functional significance of two unlinked human vitamin D receptor (hVDR) gene polymorphisms was evaluated in twenty human fibroblast cell lines. Genotypes at both a Fok I restriction site (F/f) in exon II and a singlet (A) repeat in exon IX (L/S) were determined, and relative transcription activities of endogenous hVDR proteins were measured usi...

Nonsteroidal analogues of 1,25(OH)2D3, lacking either the full five-membered D ring (C-ring analogues) or the full six-membered C ring (D-ring analogues) are more potent inhibitors of cell proliferation or inducers of cell differentiation than is 1,25(OH)2D3. Maximal superagonistic activity was seen for the C-ring analogue with a 24(R)-hydroxyl gro...

We have combined molecular modeling and classical structure-function techniques to define the interactions between the ligand-binding domain (LBD) of the vitamin D nuclear receptor (VDR) and its natural ligand, 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25-(OH)(2)D-3]. The affinity analogue 1 alpha,25-(OH)(2)D-3-3-bromoacetate exclusively labeled Cys...

The human vitamin D receptor (hVDR) is a ligand-regulated transcription factor that mediates the actions of the 1,25-dihydroxyvitamin D3 hormone to effect bone mineral homeostasis. Employing mutational analysis, we characterized Arg-18/Arg-22, hVDR residues immediately N-terminal of the first DNA binding zinc finger, as vital for contact with human...

Human vitamin D receptor (hVDR) fused to glutathione S-transferase was utilized to detect a VDR-interacting protein (VIP) of approximately 170 kDa. VIP(170) is expressed in osteoblast-like ROS 17/2.8 cells and, to a lesser extent, in COS-7 and HeLa cells. VIP(170) may be a coactivator because it interacts only with 1,25-dihydroxyvitamin D(3) (1,25(...

The vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D(3) and mediates its actions on gene transcription by heterodimerizing with retinoid X receptors (RXRs) on direct repeat (DR+3) vitamin D responsive elements (VDREs) located in target genes. The VDRE binding function of VDR has been primarily ascribed to the zinc finger region (residues 24-8...

The vitamin D receptor (VDR) is a transcription factor believed to function as a heterodimer with the retinoid X receptor (RXR). However, it was reported [Schräder et al., 1994] that, on putative vitamin D response elements (VDREs) within the rat 9k and mouse 28k calcium binding protein genes (rCaBP 9k and mCaBP 28k), VDR and thyroid hormone recept...

The characterization of the superfamily of nuclear receptors, in particular the steroid/retinoid/thyroid hormone receptors, has resulted in a more complete understanding of how a repertoire of hormonally and nutritionally derived lipophilic ligands controls cell functions to effect development and homeostasis. As transducers of hormonal signaling i...

We showed previously that liganded vitamin D receptor (VDR) effects a suppression of human atrial natriuretic peptide (hANP) gene-promoter activity in cultured neonatal rat atrial myocytes. In the present study, we have attempted to identify the structural domains of the VDR that are involved in mediating this suppression. We examined the effects o...

The human vitamin D receptor (hVDR) possesses a unique array of five basic amino acids positioned between the two DNA-binding zinc fingers that is similar to well-characterized nuclear localization sequences in other proteins. When residues within this region are mutated to nonbasic amino acids, or when this domain is deleted, the receptor is still...