Renal 25-hydroxyvitamin D3 1alpha-hydroxylase [1alpha(OH)ase] catalyzes metabolic activation of 25-hydroxyvitamin D3 into 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], an active form of vitamin D, and is inhibited by 1alpha,25(OH)2D3. 1alpha(OH)ase, which was cloned from the kidney of mice lacking the vitamin D receptor (VDR-/- mice), is a member of the P450 family of enzymes (P450VD1alpha). Expression of 1alpha(OH)ase was suppressed by 1alpha, 25(OH)2D3 in VDR+/+ and VDR+/- mice but not in VDR-/- mice. These results indicate that the negative feedback regulation of active vitamin D synthesis is mediated by 1alpha(OH)ase through liganded VDR.
Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.
Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene are a cause of pseudovitamin D-deficiency rickets.
Oleanolic acid (1) was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), and Ternstromia gymnanthera (aerial part). It inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.7 microg/mL, and inhibited H9 cell growth with an IC50 value of 21.8 microg/mL [therapeutic index (T. I.) 12.8]. Pomolic acid, isolated from R. woodsii and H. capitata, was also identified as an anti-HIV agent (EC50 1.4 microg/mL, T. I. 16.6). Although ursolic acid did show anti-HIV activity (EC50 2.0 microg/mL), it was slightly toxic (IC50 6.5 microg/mL, T. I. 3.3). A new triterpene (11) was also isolated from the CHCl3-soluble fraction of R. woodsii, though it showed no anti-HIV activity. The structure of 11 was determined to be 1beta-hydroxy-2-oxopomolic acid by spectral examination. Based on these results, we examined the anti-HIV activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S. claviflorum as an anti-HIV principle, exhibited extremely potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 18 demonstrated most potent anti-HIV activity, with an EC50 value of 0. 0005 microg/mL and a T. I. value of 22 400.
For the transactivation function of VDR, only the ligand-binding domain (E region) is thought to be responsible in a ligandbinding-dependent way (27), although two transactivation domains, one at the N terminus (AF-1) and one at the C terminus (AF-2), are present in most nuclear receptors. To achieve ligand-induced transactivation, the nuclear receptors recruit several nuclear receptor coactivators. They include members of the SRC-1/TIF2 family (38, 48), CBP/p300 (9, 29), and RIP140 (8). Members of the SRC-1/TIF2 family [SRC-1 (p160, ERAP160) (18, 23), TIF2 (Grip-1) (10), and AIB-1 (ACTR) (3)] mediate the function of the AF-2 of the nuclear receptors, and the interaction site has been mapped to the minimal activation domain (AD) of AF-2 (13, 23, 50). Interestingly, it was recently shown that the interactions of estrogen receptor with SRC-1 or TIF2 are induced by estrogen (E 2 ) but not by its antagonists, tamoxifen and ICI164,384. These findings indicate that the structure of the ligand-bound E region recruiting coactivators is ligand specific (18). This idea is further supported by recent findings from crystallographic analysis that the position of the AF-2 AD (helix 12) in the estrogen receptor E region which binds the E 2 antagonists clearly differs from the one which binds E 2 (17). From the structural similarity of the ligand-binding domains of nuclear receptors, ligand type-specific alterations in their structures, at least in the helix 12 positions, are postulated (7).Several synthetic 1␣,25(OH) 2 D 3 derivatives, such as F 6 -1␣,25-(OH) 2 D 3 [26,26,26,27,27,25(OH) OCT (25,40,44). Taking these facts together, it is reasonable to speculate that the selective interactions of VDR with coactivators induced by vitamin D analogs specify the biological activities of the vitamin D analogs. Such differential combinations of transcription factors and coactivators are believed to activate only particular sets of target gene promoters (46).To test this possibility, we studied the interaction of vitamin D analog-bound VDR with nuclear receptor coactivators and interacting factors. We found that although the in vivo and in vitro interactions of VDR with SRC-1, TIF2, and AIB-1 were induced by F 6 -1␣,25(OH) 2 D 3 and ED-71 as well as by 1␣,25 (OH) 2 D 3 , OCT induced interaction only with TIF2. Such interactions were also observed in the VDR-RXR heterodimer bound to DNA. Consistent with the interactions, only TIF2 potentiated the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the VDR structure is altered in a vitamin D analog-specific way, resulting in selective interaction of VDR with coactivators. Such selective coactivator interaction with VDR may specify the array of biological actions of a vitamin D analog such as OCT, possibly through activating a particular set of target gene promoters. MATERIALS AND METHODSYeast two-hybrid system and -galactosidase assay. The pGBT9(GAL4-DBD)-VDR(DEF) fusion plasmid was constructed by inserting rat VDR-DEF regions (encoding amino acids ...
Four new euphane-type triterpenes, kansenone (1), kansenonol (3), 11-oxo-kansenonol (4), kansenol (5), and a new tirucallane-type triterpene, epi-kansenone (2), were isolated from a 60% EtOH extract of Euphorbia kansui, together with alpha-euphol. Their structures were elucidated on the basis of extensive analysis of their 1D and 2D NMR spectral data. This appears to be the first report of the natural occurrence of euphane/tirucallane-type triterpenes with a ketone at C-7. In vitro treatment of cultured individual Xenopus laevis cells at the blastular stage with 1-4 significantly arrested cleavage of the cells (10 microg/mL of each compound resulted in >50% cleavage arrest).
Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form of KCS (KCS type 2 [KCS2]) is distinguished from the autosomal recessive form of KCS (KCS type 1 [KCS1]), which is caused by mutations of the tubulin-folding cofactor E (TBCE) gene, by the absence of mental retardation. In this study, we recruited four unrelated Japanese patients with typical sporadic KCS2, and performed exome sequencing in three patients and their parents to elucidate the molecular basis of KCS2. The possible candidate genes were explored by a de novo mutation detection method. A single gene, FAM111A (NM_001142519.1), was shared among three families. An identical missense mutation, R569H, was heterozygously detected in all three patients but not in the unaffected family members. This mutation was also found in an additional unrelated patient. These findings are in accordance with those of a recent independent report by a Swiss group that KCS2 is caused by a de novo mutation of FAM111A, and R569H is a hot spot mutation for KCS2. Although the function of FAM111A is not known, this study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation.
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