Targeted ablation of the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction.

Abstract:

:The active form of vitamin D, 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)2D], is synthesized from its precursor 25 hydroxyvitamin D [25(OH)D] via the catalytic action of the 25(OH)D-1alpha-hydroxylase [1alpha(OH)ase] enzyme. Many roles in cell growth and differentiation have been attributed to 1,25(OH)2D, including a central role in calcium homeostasis and skeletal metabolism. To investigate the in vivo functions of 1,25(OH)2D and the molecular basis of its actions, we developed a mouse model deficient in 1alpha(OH)ase by targeted ablation of the hormone-binding and heme-binding domains of the 1alpha(OH)ase gene. After weaning, mice developed hypocalcemia, secondary hyperparathyroidism, retarded growth, and the skeletal abnormalities characteristic of rickets. These abnormalities are similar to those described in humans with the genetic disorder vitamin D dependent rickets type I [VDDR-I; also known as pseudovitamin D-deficiency rickets (PDDR)]. Altered non-collagenous matrix protein expression and reduced numbers of osteoclasts were also observed in bone. Female mutant mice were infertile and exhibited uterine hypoplasia and absent corpora lutea. Furthermore, histologically enlarged lymph nodes in the vicinity of the thyroid gland and a reduction in CD4- and CD8-positive peripheral T lymphocytes were observed. Alopecia, reported in vitamin D receptor (VDR)-deficient mice and in humans with VDDR-II, was not seen. The findings establish a critical role for the 1alpha(OH)ase enzyme in mineral and skeletal homeostasis as well as in female reproduction and also point to an important role in regulating immune function.

authors

Panda DK,Miao D,Tremblay ML,Sirois J,Farookhi R,Hendy GN,Goltzman D

doi

10.1073/pnas.131029498

keywords:

subject

Has Abstract

pub_date

2001-06-19 00:00:00

pages

7498-503

issue

13

eissn

0027-8424

issn

1091-6490

pii

98/13/7498

journal_volume

98

pub_type

杂志文章
  • Protein cleavage during virus assembly: a novel specificity of assembly dependent cleavage in bacteriophage T4.

    abstract::Cleavage of precursor proteins occurs during assembly of numerous viruses. Seven bacteriophage T4 head-related proteins areknown to be cleaved during morphogenesis. Sequences surrounding the cleavage sites in T4 head precursors P23 and IPIII are reported here. We previously determined the sequences of precursor and pr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.11.4205

    authors: Isobe T,Black LW,Tsugita A

    更新日期:1976-11-01 00:00:00

  • Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria.

    abstract::Infection of mice with sporozoites of Plasmodium berghei or Plasmodium yoelii has been used extensively to evaluate liver-stage protection by candidate preerythrocytic malaria vaccines. Unfortunately, repeated success of such vaccines in mice has not translated readily to effective malaria vaccines in humans. Thus, mi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0805452105

    authors: Schmidt NW,Podyminogin RL,Butler NS,Badovinac VP,Tucker BJ,Bahjat KS,Lauer P,Reyes-Sandoval A,Hutchings CL,Moore AC,Gilbert SC,Hill AV,Bartholomay LC,Harty JT

    更新日期:2008-09-16 00:00:00

  • Limits to gene flow in a cosmopolitan marine planktonic diatom.

    abstract::The role of geographic isolation in marine microbial speciation is hotly debated because of the high dispersal potential and large population sizes of planktonic microorganisms and the apparent lack of strong dispersal barriers in the open sea. Here, we show that gene flow between distant populations of the globally d...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1001380107

    authors: Casteleyn G,Leliaert F,Backeljau T,Debeer AE,Kotaki Y,Rhodes L,Lundholm N,Sabbe K,Vyverman W

    更新日期:2010-07-20 00:00:00

  • Selection against variants in the genome associated with educational attainment.

    abstract::Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainm...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1612113114

    authors: Kong A,Frigge ML,Thorleifsson G,Stefansson H,Young AI,Zink F,Jonsdottir GA,Okbay A,Sulem P,Masson G,Gudbjartsson DF,Helgason A,Bjornsdottir G,Thorsteinsdottir U,Stefansson K

    更新日期:2017-01-31 00:00:00

  • Lipophosphoglycan of Leishmania major that vaccinates against cutaneous leishmaniasis contains an alkylglycerophosphoinositol lipid anchor.

    abstract::The major cell surface glycoconjugate of Leishmania major, a putative parasite receptor for macrophages, is a lipophosphoglycan containing 81.6% (wt/wt) carbohydrate, 17.0% (wt/wt) phosphate, and 1.4% (wt/wt) lipid. It has been purified to homogeneity by hydrophobic chromatography and consists of a polydisperse family...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.24.8941

    authors: McConville MJ,Bacic A,Mitchell GF,Handman E

    更新日期:1987-12-01 00:00:00

  • Trim5alpha protein restricts both HIV-1 and murine leukemia virus.

    abstract::Replication of HIV-1 and N-tropic murine leukemia virus (N-MLV) is restricted in a number of different primate cells. In some cell lines, cross-saturation experiments suggest that the two viruses are interacting with the same restriction factor. Recently, Trim5alpha protein from rhesus monkey was found to restrict HIV...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0402876101

    authors: Yap MW,Nisole S,Lynch C,Stoye JP

    更新日期:2004-07-20 00:00:00

  • Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation.

    abstract::Claspin is a homolog of Mrc1, a checkpoint protein required for the DNA replication checkpoint in yeast. In Xenopus, phosphorylated Claspin binds to xChk1 and regulates xChk1 activation in response to replication stress. In this study, we have shown that the human homolog of Claspin is required for resistance to multi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0401847101

    authors: Lin SY,Li K,Stewart GS,Elledge SJ

    更新日期:2004-04-27 00:00:00

  • Trigger loop dynamics mediate the balance between the transcriptional fidelity and speed of RNA polymerase II.

    abstract::During transcription, RNA polymerase II (RNAPII) must select the correct nucleotide, catalyze its addition to the growing RNA transcript, and move stepwise along the DNA until a gene is fully transcribed. In all kingdoms of life, transcription must be finely tuned to ensure an appropriate balance between fidelity and ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1200939109

    authors: Larson MH,Zhou J,Kaplan CD,Palangat M,Kornberg RD,Landick R,Block SM

    更新日期:2012-04-24 00:00:00

  • traG protein of the F sex factor of Escherichia coli K-12 and its role in conjugation.

    abstract::The traG protein of the F sex factor is an inner membrane protein with a molecular weight of 116,000. Mutants in traG (or in traN) are able to trigger conjugal DNA replication even though they cannot efficiently form stable mating aggregates with F(-) cells. The traG protein (and the traN protein) probably acts in the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.12.7487

    authors: Manning PA,Morelli G,Achtman M

    更新日期:1981-12-01 00:00:00

  • Absence of histones from the chromosomal proteins of fungi.

    abstract::Interphase chromosomes were isolated in good yield from four species of fungi. In no case does the chromatin contain histones such as are characteristic of the chromosomes of other eukaryotic organisms. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.68.3.677

    authors: Leighton TJ,Dill BC,Stock JJ,Phillips C

    更新日期:1971-03-01 00:00:00

  • Swimming bacteria power microscopic gears.

    abstract::Whereas the laws of thermodynamics prohibit extraction of useful work from the Brownian motion of particles in equilibrium, these motions can be "rectified" under nonequilibrium conditions, for example, in the presence of asymmetric geometrical obstacles. Here, we describe a class of systems in which aerobic bacteria ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0913015107

    authors: Sokolov A,Apodaca MM,Grzybowski BA,Aranson IS

    更新日期:2010-01-19 00:00:00

  • A ribosome-dependent GTPase from yeast distinct from elongation factor 2.

    abstract::Three proteins required for poly(U)-directed polyphenylalanine synthesis have been separated from yeast. Two of the factors correspond to the elongation factors 1 and 2 described for other eukaryotic systems, according to the criteria of phenylalanyl-tRNA binding and diphtheria toxin-catalyzed ADP-ribosylation. The th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.1.73

    authors: Skogerson L,Wakatama E

    更新日期:1976-01-01 00:00:00

  • Parallel processing of serial movements in prefrontal cortex.

    abstract::A key idea in Lashley's formulation of the problem of serial order in behavior is the postulated neural representation of all serial elements before the action begins. We studied this question by recording the activity of individual neurons simultaneously in small ensembles in prefrontal cortex while monkeys copied ge...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.162485599

    authors: Averbeck BB,Chafee MV,Crowe DA,Georgopoulos AP

    更新日期:2002-10-01 00:00:00

  • yes-related protooncogene, syn, belongs to the protein-tyrosine kinase family.

    abstract::An src/yes-related novel gene named syn (SYN in human gene nomenclature) has been identified in the human genome on chromosome 6 and characterized by molecular cloning. Nucleotide sequence analysis of cDNA clones showed that the c-syn gene could encode a protein-tyrosine kinase that is very similar in primary structur...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.15.5459

    authors: Semba K,Nishizawa M,Miyajima N,Yoshida MC,Sukegawa J,Yamanashi Y,Sasaki M,Yamamoto T,Toyoshima K

    更新日期:1986-08-01 00:00:00

  • Warfare and reproductive success in a tribal population.

    abstract::Intergroup conflict is a persistent feature of many human societies yet little is known about why individuals participate when doing so imposes a mortality risk. To evaluate whether participation in warfare is associated with reproductive benefits, we present data on participation in small-scale livestock raids among ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1412287112

    authors: Glowacki L,Wrangham R

    更新日期:2015-01-13 00:00:00

  • Extreme clonal diversity and divergence in populations of a selfing hermaphroditic fish.

    abstract::Recombination is unknown in natural populations of Rivulus marmoratus, a selfing hermaphrodite, and genetic variation is likely due to mutation alone. DNA fingerprinting with an array of microsatellite [e.g., (CT)9] and minisatellite (e.g., the 33.15 core sequence) probes reveals very high clonal diversity within samp...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.22.10643

    authors: Turner BJ,Elder JF Jr,Laughlin TF,Davis WP,Taylor DS

    更新日期:1992-11-15 00:00:00

  • Constituents and functional implications of the rat default mode network.

    abstract::The default mode network (DMN) has been suggested to support a variety of self-referential functions in humans and has been fractionated into subsystems based on distinct responses to cognitive tasks and functional connectivity architecture. Such subsystems are thought to reflect functional hierarchy and segregation w...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1601485113

    authors: Hsu LM,Liang X,Gu H,Brynildsen JK,Stark JA,Ash JA,Lin CP,Lu H,Rapp PR,Stein EA,Yang Y

    更新日期:2016-08-02 00:00:00

  • Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria.

    abstract::Cyclodextrins are cyclic oligosaccharides widely used in the pharmaceutical industry to improve drug delivery and to increase the solubility of hydrophobic compounds. Anabaenolysins are lipopeptides produced by cyanobacteria with potent lytic activity in cholesterol-containing membranes. Here, we identified the 23- to...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1510432112

    authors: Shishido TK,Jokela J,Kolehmainen CT,Fewer DP,Wahlsten M,Wang H,Rouhiainen L,Rizzi E,De Bellis G,Permi P,Sivonen K

    更新日期:2015-11-03 00:00:00

  • Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150- to 170-kDa protein detected by photoaffinity labeling.

    abstract::Multiple drug resistance of tumor cells is a common problem in cancer therapy. We have demonstrated that membrane vesicles from highly multidrug-resistant human KB carcinoma cell lines exhibit increased specific and saturable binding of vinblastine. To identify the molecules that bind vinblastine, membrane vesicles fr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.11.3847

    authors: Cornwell MM,Safa AR,Felsted RL,Gottesman MM,Pastan I

    更新日期:1986-06-01 00:00:00

  • Maintenance of host variation in tolerance to pathogens and parasites.

    abstract::Tolerance and resistance provide hosts with two distinct defense strategies against parasitism. In resistance the hosts "fight" the parasite directly, whereas in tolerance the hosts fight the disease by ameliorating the damage that infection causes. There is increasing recognition that the two mechanisms may exhibit v...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0809558105

    authors: Best A,White A,Boots M

    更新日期:2008-12-30 00:00:00

  • Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists.

    abstract::Antischizophrenic neuroleptic drugs of the diphenylbutylpiperidine class, which includes pimozide, fluspirilene, penfluridol, and clopimozide, inhibit [3H]nitrendipine binding with IC50 values of 13-30 nM. This inhibition involves receptors for the verapamil/prenylamine class of calcium channel antagonists. These diph...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.16.5122

    authors: Gould RJ,Murphy KM,Reynolds IJ,Snyder SH

    更新日期:1983-08-01 00:00:00

  • Isolation and characterization of the human parathyroid hormone-like peptide gene.

    abstract::A parathyroid hormone-like peptide (PTH-LP) has recently been identified in human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The peptide appears to be encoded by a single-copy gene that gives rise to multiple mRNAs that are heterogeneous at both their 5' and their 3' ends. Alternative ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.7.2408

    authors: Mangin M,Ikeda K,Dreyer BE,Broadus AE

    更新日期:1989-04-01 00:00:00

  • Extremely high-gain source-gated transistors.

    abstract::Despite being a fundamental electronic component for over 70 years, it is still possible to develop different transistor designs, including the addition of a diode-like Schottky source electrode to thin-film transistors. The discovery of a dependence of the source barrier height on the semiconductor thickness and deri...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1820756116

    authors: Zhang J,Wilson J,Auton G,Wang Y,Xu M,Xin Q,Song A

    更新日期:2019-03-12 00:00:00

  • Flame-formed carbon nanoparticles exhibit quantum dot behaviors.

    abstract::We examine the quantum confinement in the photoemission ionization energy in air and optical band gap of carbon nanoparticles (CNPs). Premixed, stretched-stabilized ethylene flames are used to generate the CNPs reproducibly over the range of 4-23 nm in volume median diameter. The results reveal that flame-formed CNPs ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1900205116

    authors: Liu C,Singh AV,Saggese C,Tang Q,Chen D,Wan K,Vinciguerra M,Commodo M,De Falco G,Minutolo P,D'Anna A,Wang H

    更新日期:2019-06-25 00:00:00

  • Effects of lipid packing on polymorphic phase behavior and membrane properties.

    abstract::The self assembly of phospholipid molecules in the bilayer form was considered in terms of equivalent molecular shapes representing intermolecular forces. The equivalent size of each phospholipid headgroup was approximated by the net atomic volume plus the volume of the associated water molecules, which was derived fr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.15.5825

    authors: Hui SW,Sen A

    更新日期:1989-08-01 00:00:00

  • Control of the initiation of DNA synthesis in 3T3 cells: low-molecular weight nutrients.

    abstract::Sparse 3T3 cells, in excess serum, become quiescent in the early G(1) (or G(0)) phase of the cell cycle if the cells are cultured in low concentrations of amino acids, glucose, or phosphate ion. These quiescent cells then initiate DNA synthesis if the concentration of the limiting nutrient is increased. In normal medi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.71.8.2942

    authors: Holley RW,Kiernan JA

    更新日期:1974-08-01 00:00:00

  • Transcriptome and metabolome profiling of field-grown transgenic barley lack induced differences but show cultivar-specific variances.

    abstract::The aim of the present study was to assess possible adverse effects of transgene expression in leaves of field-grown barley relative to the influence of genetic background and the effect of plant interaction with arbuscular mycorrhizal fungi. We conducted transcript profiling, metabolome profiling, and metabolic finge...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1001945107

    authors: Kogel KH,Voll LM,Schäfer P,Jansen C,Wu Y,Langen G,Imani J,Hofmann J,Schmiedl A,Sonnewald S,von Wettstein D,Cook RJ,Sonnewald U

    更新日期:2010-04-06 00:00:00

  • AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption.

    abstract::Filtration through the kidney eliminates toxins, manages electrolyte balance, and controls water homeostasis. Reabsorption of water from the luminal fluid of the nephron occurs through aquaporin-2 (AQP2) water pores in principal cells that line the kidney-collecting duct. This vital process is impeded by formation of ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1607745113

    authors: Whiting JL,Ogier L,Forbush KA,Bucko P,Gopalan J,Seternes OM,Langeberg LK,Scott JD

    更新日期:2016-07-26 00:00:00

  • A20-binding inhibitor of NF-κB (ABIN1) controls Toll-like receptor-mediated CCAAT/enhancer-binding protein β activation and protects from inflammatory disease.

    abstract::Toll-like receptors (TLRs) are expressed on innate immune cells and trigger inflammation upon detection of pathogens and host tissue injury. TLR-mediated proinflammatory-signaling pathways are counteracted by partially characterized anti-inflammatory mechanisms that prevent exaggerated inflammation and host tissue dam...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1106232108

    authors: Zhou J,Wu R,High AA,Slaughter CA,Finkelstein D,Rehg JE,Redecke V,Häcker H

    更新日期:2011-11-01 00:00:00

  • Stimulation and inhibition of anti-hapten responses in guinea pigs immunized with hybrid liposomes.

    abstract::Guinea pigs were immunized with liposomal model membranes containing phosphatidylethanolamine (PE) or glycerophosphorylethanolamine (GPE) derivatives in which the amino function was substituted with either dinitrophenylaminocaproyl (Dnp-Cap) or mono(p-azobenzenearsonic acid)tyrosyl (ABA-Tyr) residues. Previous studies...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.72.11.4582

    authors: Kochibe N,Nicolotti RA,Davie JM,Kinsky SC

    更新日期:1975-11-01 00:00:00