Disease relevance of CYP27B1

• We found preliminary evidence for enzymatic activity of endogenous CYP27B1 in glioblastoma multiforme cell cultures but not for the functionality of the splice variants [1].
• These studies provide the basis for a more detailed understanding of CYP27B1 repression in prostate cancer cells and could provide a novel insight in future diagnosis and treatment [2].
• These are the first studies to demonstrate that nontransformed human mammary cells express CYP27B1, that they are growth inhibited by physiologically relevant concentrations of 25(OH)D3, and that they provide a biological mechanism linking vitamin D status to breast cancer risk [3].
• A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans [4].
• We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus [4].

Psychiatry related information on CYP27B1

• Psychiatric examination and molecular genetic studies were performed in this family overloaded with psychotic disorders and VDDR IIA [5].
• Electroconvulsive therapy (ECT) in a patient with a dual-chamber sensing, VDDR pacemaker [6].

High impact information on CYP27B1

• A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system [7].
• The 1,25-dihydroxyvitamin D3 receptor (VDR) gene locus was previously found to be associated with bone density [8].
• Pseudo-vitamin D-deficiency rickets (PDDR) was mapped close to D12S90 and between proximal D12S312 and distal (D12S305, D12S104) microsatellites that were subsequently found on a single YAC clone [9].
• An indication of linkage with the PDDR phenotype was found for one of the polymorphic bands, denoted 30A [10].
• A significant linkage [logarithm-of-odds (lod) score greater than 3.0] was obtained between this polymorphism and a number of chromosome 12q markers tightly linked to PDDR [10].

Chemical compound and disease context of CYP27B1

• Vitamin D(3) metabolism in human glioblastoma multiforme: functionality of CYP27B1 splice variants, metabolism of calcidiol, and effect of calcitriol [1].
• Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells [2].
• In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D(3) for antimitotic action is determined through the activity of the two enzymes CYP24 and CYP27B1, viz [11].
• Pseudovitamin D-defiency rickets (PDDR) is an autosomal recessive disorder characterized by hypocalcemia, rickets (which are resistant to treatment with vitamin D), and low or undetectable serum levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) [12].
• Sequence variants in the human 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27B1) gene are not associated with prostate cancer risk [13].

Biological context of CYP27B1

• Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3: biochemical, histomorphometric, and biomechanical analyses [14].
• The regulation of the gene for renal 25-hydroxyvitamin D 1alpha- hydroxylase (1alpha(OH)ase; CYP27B1) by parathyroid hormone (PTH) under hypocalcemic conditions is fundamentally important for the maintenance of calcium and phosphate homeostasis [15].
• We propose that the formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to silencing of either the nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D [2].
• First, we identify a repressive region between -997 and -1200 in the human CYP27B1 promoter following transient transfection analysis in the prostate cancer cell lines DU145, PC3 and LNCaP [2].
• BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation [4].

Anatomical context of CYP27B1

• A cell line was treated with calcitriol to determine the effect on the expression of CYP27B1, 1alpha,25-dihydroxyvitamin D(3)-24-hydroxylase (CYP24), and vitamin D(3) receptor (VDR) [1].
• Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3 [3].
• In contrast, basal 1alpha-hydroxylase CYP27B1 expression levels were found to be 65% higher in the colon than in the small intestine (P < 0.02) [16].
• Besides the almost universal presence of VDRs, some cell types (e.g. keratinocytes, monocytes, bone, placenta) are capable of metabolizing 25-hydroxyvitamin D to 1,25(OH)(2)D by the enzyme 1alpha-hydroxylase (CYP27B1) [17].
• The aim of this study was to investigate what factors regulate expression of the CYP27B1 gene in osteoblast cells [18].

Associations of CYP27B1 with chemical compounds

• The administration of calcitriol led to an elevated expression of CYP27B1 and CYP24 but left the expression of the VDR unaltered [1].
• EXPERIMENTAL DESIGN: We did nested touchdown reverse transcription-PCR (RT-PCR) to identify CYP27B1 splice variants and real-time RT-PCR to quantify the expression of CYP27B1 [1].
• 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) is the enzyme responsible for the regulation of cellular 1,25D levels [2].
• CYP27B1 is a cytochrome P450-containing hydroxylase expressed in kidney and other tissues that generates 1alpha,25(OH)2D3 from an inactive vitamin D precursor 25-hydroxycholecalciferol [25(OH)D3] [3].
• CYP27B1 mRNA silencing by RNAi, resulted in the suppression of 1,25D production and subsequent reduction of OCN and CYP24 mRNA expression [19].

Physical interactions of CYP27B1

• Site directed mutagenesis of the core GFI1 binding sequence (5'-AATC-3') substantially increased while forced expression of GFI1 decreased the expression of the CYP27B1 reporter construct [2].

Regulatory relationships of CYP27B1

• 1alpha,25-Dihydroxyvitamin D(3) downregulates CYP27B1 and induces CYP24A1 in colon cells [20].
• PTH and forskolin stimulated CYP1alpha promoter activity via a cAMP-dependent pathway acting through the phosphorylation of CREB (cAMP-dependent response element-binding protein) [21].

Other interactions of CYP27B1

• Human placenta synthesizes and metabolizes 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)/calcitriol] through the activity of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (CYP27B1) and 1,25(OH)(2)D(3)-24-hydroxylase (CYP24A1), the two key enzymes for Vitamin D metabolism [22].
• In contrast, UVB and calcitriol had no effect on gene expression of CYP27A1 and CYP27B1 [23].
• CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients [24].
• Our results implicate TOM1L2 and CYP27B1 as having roles as novel targets for the 17p and 12q amplicons, respectively [25].
• Further subtraction of normal endothelium, bone marrow, white blood cell and other normal tissue transcripts resulted in just three gene transcripts, ANAPC10, PLXDC1(TEM7), and CYP27B1, that are highly specific to GBM-ECs [26].

Analytical, diagnostic and therapeutic context of CYP27B1

• Using Western blot and quantitative real-time PCR, CYP27B1 mRNA and protein were detected in immortalized, nontumorigenic human mammary epithelial cell (HMEC) cultures [3].
• In the research presented here, we have investigated the influence of UVB-triggered calcitriol production on gene expression of the vitamin D3 hydroxylating enzymes catabolic 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), active vitamin-D3-25-hydroxylase (CYP27A1), and 25-hydroxyvitamin-D3-1alpha-hydroxylase (CYP27B1) using real-time PCR [23].
• As shown by HPLC, CYP27B1 is active only if basal 24-hydroxylation is not maximally functional [20].
• Although the sequence alignment suggested that Arg107, Gly125, and Pro497 of CYP27B1 might be involved in substrate binding, the experimental data strongly suggested that mutations of these amino-acid residues destroyed the tertiary structure of the substrate-heme pocket [27].
• We have previously engineered an animal model of PDDR by targeted inactivation of the 1alpha-OHase gene in mice [14].

References