Kinetics and regulation of 25-hydroxycholecalciferol 1alpha-hydroxylase from cells isolated from human term decidua

Delvin, Edgard; Arabian, Alice

doi:10.1111/j.1432-1033.1987.tb10915.x

Cited by 39 publications

(12 citation statements)

References 28 publications

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“…3A). However, this value is comparable to that obtained previously in chick and pig kidney and human placenta and skin (27,(38)(39)(40). Thus, the cloned cDNA encodes an enzyme, P450c1␣, with robust 1␣-hydrox-ylase activity.…”

Section: Expression Of P450c1␣ Cdna In Mammalian Cellssupporting

confidence: 86%

Cloning of Human 25-Hydroxyvitamin D-1α-Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1

Lin

Zhang

et al. 1997

Molecular Endocrinology

141

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The secosteroid hormone, 1,25-dihydroxyvitamin D [1,25(OH)2D], plays a crucial role in normal bone growth, calcium metabolism, and tissue differentiation. The key step in the biosynthesis of 1,25(OH)2D is its 1 alpha-hydroxylation from 25-hydroxyvitamin D (25-OHD) in the kidney. Because its expression in the kidney is very low, we cloned and sequenced cDNA for 25-OHD-1 alpha-hydroxylase (P450c1 alpha) from human keratinocytes, in which 1 alpha-hydroxylase activity and mRNA expression can be induced to be much greater. P450c1 alpha mRNA was expressed at much lower levels in human kidney, brain, and testis. Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. The identity of the 1,25(OH)2D3 product synthesized in transfected cells was confirmed by HPLC and gas chromatography-mass spectrometry. The gene encoding P450c1 alpha was localized to chromosome 12, where the 1 alpha-hydroxylase deficiency syndrome, vitamin D-dependent rickets type 1 (VDDR-1), has been localized. Primary cultures of human adult and neonatal keratinocytes exhibit abundant 1 alpha-hydroxylase activity, whereas those from a patient with VDDR-1 lacked detectable activity. Keratinocyte P450c1 alpha cDNA from the patient with VDDR-1 contained deletion/frameshift mutations either at codon 211 or at codon 231, indicating that the patient was a compound heterozygote for two null mutations. These findings establish the molecular genetic basis of VDDR-1, establish a novel means for its study in keratinocytes, and provide the sequence of the key enzyme in the biological activation of vitamin D.

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Section: Expression Of P450c1␣ Cdna In Mammalian Cellssupporting

confidence: 86%

Cloning of Human 25-Hydroxyvitamin D-1α-Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1

Lin

Zhang

et al. 1997

Molecular Endocrinology

141

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“…Organic phases were collected, pooled, and evaporated to dryness in a 37°C water bath under a stream of nitrogen. Samples were redissolved in 45% diethylether in hexane and purified by silicic acid column chromatography as previously described 9. The purified fractions were resuspended in 100 μl of 9.5% isopropanol in hexane 9.…”

Section: Methodsmentioning

confidence: 99%

The 25-Hydroxyvitamin D 1-Alpha-Hydroxylase Gene Maps to the Pseudovitamin D-Deficiency Rickets (PDDR) Disease Locus

St‐Arnaud¹,

Messerlian²,

Moir³

et al. 1997

Journal of Bone and Mineral Research

299

135

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“…Not only 1,25D inhibits endometrial CYP27B1 activity at physiological levels, 52 but also suppresses CYP2R1 expression in fibroblasts and prostate cancer cells. 53 Thus, 1,25D treatment could simultaneously compromise endometrial 1,25D production and aggravate systemic VD deficiency.…”

Section: Local Vitamin D Actions In Endometrial Cancermentioning

confidence: 99%

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

Bergadà

Pallarés

Arcidiacono

et al. 2014

Laboratory Investigation

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Vitamin D (VD) deficiency has been suggested as a risk factor for cancer. One recognized mechanism is that the low-serum 25-hydroxyvitamin D (25(OH)D) of VD deficiency reduces intratumoral 25(OH)D conversion to 1a,25-dihydroxyvitamin D (1,25D, the hormonal form of VD), compromising 1,25D-VD receptor (VDR) antitumoral actions. Reduced tumoral VDR and increased CYP24A1, the enzyme that degrades 1,25D and 25(OH)D, further worsen cancer progression. Importantly, in cells expressing CYP27A1 and/or CYP2R1, which convert inert VD into 25(OH)D, low-serum VD may reduce intratumoral 25(OH)D synthesis thereby compromising VDR antitumoral actions because 25(OH)D can activate the VDR directly and enhance 1,25D-VDR action. Therefore, this study examined whether abnormal endometrial expression of CYP27A1 and/or CYP2R1 may impair VDR-antiproliferative properties in endometrial carcinoma (EC). Immunohistochemical analysis of tissue microarrays of normal human endometrium (NE; n ¼ 60) and EC (n ¼ 157) showed the expected lower VDR expression in EC (P ¼ 0.0002). Instead, CYP24A1 expression was lower in EC compared with NE, while CYP27A1 and CYP2R1 expressions were higher (P ¼ 0.0002; P ¼ 0.03). Furthermore, in NE and EC, CYP2R1 and CYP27A1 expression correlated directly with nuclear VDR levels, an indicator of ligand-induced VDR activation, and inversely with the proliferation marker Ki67. Accordingly, in the endometrioid carcinoma cell lines IK, RL95/2 and HEC1-A, which express VDR, CYP27A1, and CYP2R1, VD efficaciously reduced cell viability and colony number, with a time course that paralleled actual increases in both intracellular 25(OH)D and nuclear VDR levels. Thus, VD may protect from EC progression in part through increased intratumoral 25(OH)D production by CYP27A1 and CYP2R1 for autocrine/paracrine enhancement of 1,25D-VDR-antiproliferative actions. Endometrial carcinoma (EC) results from neoplastic transformation of normal endometrium (NE) 1 leading to two main clinicopathological variants: endometrioid carcinoma (EEC) and non-endometrioid carcinomas (NEEC). EECs are estrogen-related tumors, frequently well differentiated, and developing mostly in peri-and postmenopausal women. Low grades (1 and 2) tumors are usually confined to the uterus (stage I) while grade 3 EECs are less frequent, with a higher tendency for extrauterine spread. NEEC, either serous or clear cell (CC) carcinomas, occur in older women, are estrogenunrelated tumors, with aggressive behavior and frequent extrauterine spread to the peritoneum or lymph nodes. 2,3 One risk factor for human cancer that can be safely modified is vitamin D (VD) deficiency/insufficiency.

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Kinetics and regulation of 25-hydroxycholecalciferol 1alpha-hydroxylase from cells isolated from human term decidua

Cited by 39 publications

References 28 publications

Cloning of Human 25-Hydroxyvitamin D-1α-Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1

Cloning of Human 25-Hydroxyvitamin D-1α-Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1

The 25-Hydroxyvitamin D 1-Alpha-Hydroxylase Gene Maps to the Pseudovitamin D-Deficiency Rickets (PDDR) Disease Locus

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

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