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Article ; Online: The current landscape of lipoprotein(a) in calcific aortic valvular disease.

Hsieh, Grace / Rizk, Theresa / Berman, Adam N / Biery, David W / Blankstein, Ron

2021 Volume 36, Issue 5, Page(s) 542–548

Abstract: Purpose of review: Calcific aortic stenosis (CAVS) is the most common form of valvular heart disease in developed countries, increasing in prevalence with the aging population. Surgical or transcatheter aortic valve replacement is the only treatment ... ...

Abstract	Purpose of review: Calcific aortic stenosis (CAVS) is the most common form of valvular heart disease in developed countries, increasing in prevalence with the aging population. Surgical or transcatheter aortic valve replacement is the only treatment available for CAVS. However, these interventions are typically reserved for severe symptomatic aortic stenosis (AS). The purpose of this review is to summarize the recent literature in uncovering the underlying pathophysiology of CAVS in the setting of lipoprotein (a) [Lp(a)] and emerging therapies targeting Lp(a) which may help halt disease progression in CAVS. Recent findings: Pathophysiologic, epidemiological, and genetic studies over the past two decades have provided strong evidence that Lp(a) is an important mediator of calcific aortic valvular disease (CAVD). Studies suggest that Lp(a) is a key carrier of pro-calcifying oxidized phospholipids (OxPL). The metabolism of OxPL results in a pro-inflammatory state and subsequent valvular thickening and mineralization through pro-osteogenic signaling. The identification of Lp(a) as a causal mediator of CAVD has allowed for opportunities for emerging therapeutic agents which may slow the progression of CAVD (Fig. 1JOURNAL/cocar/04.03/00001573-202109000-00007/figure1/v/2021-08-04T080204Z/r/image-jpeg). Summary: This review summarizes the current knowledge on the association of Lp(a) with CAVD and ongoing studies of potential Lp(a)-lowering therapies. Based on the rate-limiting and causal role of Lp(a) in progression of CAVS, these therapies may represent novel pharmacotherapies in AS and inform the developing role of Lp(a) in the clinical management of CAVD.
MeSH term(s)	Aged ; Aortic Valve/surgery ; Aortic Valve Stenosis/diagnosis ; Aortic Valve Stenosis/epidemiology ; Aortic Valve Stenosis/surgery ; Calcinosis ; Humans ; Lipoprotein(a) ; Phospholipids
Chemical Substances	Lipoprotein(a) ; Phospholipids
Language	English
Publishing date	2021-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645186-x
ISSN	1531-7080 ; 0268-4705
ISSN (online)	1531-7080
ISSN	0268-4705
DOI	10.1097/HCO.0000000000000901
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Article ; Online: Flipping Out: Does the Flipped Classroom Learning Model Work for GME?

Cooper, Avraham Z / Hsieh, Grace / Kiss, Joshua E / Huang, Grace C

Journal of graduate medical education

2017 Volume 9, Issue 3, Page(s) 392–393

MeSH term(s)	Cardiology/education ; Computer-Assisted Instruction ; Curriculum ; Education, Medical, Graduate/trends ; Education, Medical, Undergraduate/trends ; Educational Measurement ; Humans ; Internal Medicine/education ; Internship and Residency ; Models, Educational ; Problem-Based Learning/trends
Language	English
Publishing date	2017-06-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2578612-X
ISSN	1949-8357 ; 1949-8357
ISSN (online)	1949-8357
ISSN	1949-8357
DOI	10.4300/JGME-D-16-00827.1
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Article ; Online: Impact of coronary artery calcium testing on patient management.

Wu, Wanda Y / Biery, David W / Berman, Adam N / Hsieh, Grace / Divakaran, Sanjay / Gupta, Sumit / Steigner, Michael L / Aghayev, Ayaz / Skali, Hicham / Polk, Donna M / Plutzky, Jorge / Cannon, Christopher P / Di Carli, Marcelo F / Blankstein, Ron

Journal of cardiovascular computed tomography

2021 Volume 16, Issue 4, Page(s) 303–308

Abstract: Background: Coronary artery calcium (CAC) scoring can identify individuals who may benefit from aggressive prevention therapies. However, there is a paucity of contemporary data on the impact of CAC testing on patient management.: Methods: ... ...

Abstract	Background: Coronary artery calcium (CAC) scoring can identify individuals who may benefit from aggressive prevention therapies. However, there is a paucity of contemporary data on the impact of CAC testing on patient management. Methods: Retrospective cohort study of adults who underwent CAC testing at Brigham and Women's Hospital between 2015 and 2019. Information on baseline medications, follow-up medications, lifestyle modification, and downstream cardiovascular testing within one-year post-CAC were obtained from electronic health records. Results: Of the 839 patients with available baseline and follow-up data, 376 (45%) had a CAC = 0, 289 (34%) had CAC = 1-99, and 174 (21%) had CAC≥100. The mean age at time of CAC testing was 59 ± 9.7 years. Patients with higher CAC scores were more likely to be male, have diabetes and hypertension, and have higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol. A non-zero CAC score was associated with initiation of aspirin (41% increase, p < 0.001), anti-hypertensives (9% increase, p = 0.031), and lipid-lowering therapies (114% increase, p < 0.001), whereas CAC = 0 was not. Among individuals with CAC≥100, 75% were started on new or more intense lipid-lowering therapy. Higher calcium scores correlated with increased physician recommendations for diet (p = 0.008) and exercise (p = 0.004). The proportion of cardiovascular downstream testing following CAC was 9.1%, and the majority of patients who underwent additional testing post-CAC had CAC scores ≥100. Conclusion: Approximately half of individuals referred for CAC testing had evidence of calcified coronary plaque, and of those who had significant calcifications (CAC≥100), nearly 90% were prescribed lipid-lowering therapies post-CAC. Rates of downstream non-invasive testing were low and such testing was mostly performed in patients who had at least moderate CAC.
MeSH term(s)	Adult ; Calcium ; Cholesterol, LDL ; Coronary Artery Disease/prevention & control ; Coronary Artery Disease/therapy ; Coronary Vessels/diagnostic imaging ; Female ; Humans ; Male ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Vascular Calcification/diagnostic imaging ; Vascular Calcification/therapy
Chemical Substances	Cholesterol, LDL ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-12-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2394360-9
ISSN	1876-861X ; 1934-5925
ISSN (online)	1876-861X
ISSN	1934-5925
DOI	10.1016/j.jcct.2021.12.006
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Zs.A 6761: Show issues

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Article ; Online: Functional genomics to explore cancer cell vulnerabilities.

Kahle, Kristopher T / Kozono, David / Ng, Kimberly / Hsieh, Grace / Zinn, Pascal O / Nitta, Masayuki / Chen, Clark C

Neurosurgical focus

2010 Volume 28, Issue 1, Page(s) E5

Abstract: Our understanding of glioblastoma multiforme (GBM), the most common form of primary brain cancer, has been significantly advanced by recent efforts to characterize the cancer genome using unbiased high-throughput sequencing analyses. While these studies ... ...

Abstract	Our understanding of glioblastoma multiforme (GBM), the most common form of primary brain cancer, has been significantly advanced by recent efforts to characterize the cancer genome using unbiased high-throughput sequencing analyses. While these studies have documented hundreds of mutations, gene copy alterations, and chromosomal abnormalities, only a subset of these alterations are likely to impact tumor initiation or maintenance. Furthermore, genes that are not altered at the genomic level may play essential roles in tumor initiation and maintenance. Identification of these genes is critical for therapeutic development and investigative methodologies that afford insight into biological function. This requirement has largely been fulfilled with the emergence of RNA interference (RNAi) and high-throughput screening technology. In this article, the authors discuss the application of genome-wide, high-throughput RNAi-based genetic screening as a powerful tool for the rapid and cost-effective identification of genes essential for cancer proliferation and survival. They describe how these technologies have been used to identify genes that are themselves selectively lethal to cancer cells, or synthetically lethal with other oncogenic mutations. The article is intended to provide a platform for how RNAi libraries might contribute to uncovering glioma cell vulnerabilities and provide information that is highly complementary to the structural characterization of the glioblastoma genome. The authors emphasize that unbiased, systems-level structural and functional genetic approaches are complementary efforts that should facilitate the identification of genes involved in the pathogenesis of GBM and permit the identification of novel drug targets.
MeSH term(s)	Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/genetics ; Cell Transformation, Neoplastic/genetics ; Drug Discovery/methods ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genes, Essential/genetics ; Genes, Lethal/genetics ; Genetic Predisposition to Disease/genetics ; Genomics/methods ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Humans ; Mutation/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Oncogenes/drug effects ; Oncogenes/genetics ; Pharmacogenetics ; RNA Interference/drug effects ; RNA, Small Interfering/genetics
Chemical Substances	RNA, Small Interfering
Language	English
Publishing date	2010-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2026589-X
ISSN	1092-0684 ; 1092-0684
ISSN (online)	1092-0684
ISSN	1092-0684
DOI	10.3171/2009.10.FOCUS09212
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Article ; Online: Analysis of hairless corepressor mutants to characterize molecular cooperation with the vitamin D receptor in promoting the mammalian hair cycle.

Hsieh, Jui-Cheng / Slater, Stephanie A / Whitfield, G Kerr / Dawson, Jamie L / Hsieh, Grace / Sheedy, Craig / Haussler, Carol A / Haussler, Mark R

Journal of cellular biochemistry

2010 Volume 110, Issue 3, Page(s) 671–686

Abstract: 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- ... ...

Abstract	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 motifs known to mediate contact of Hr with the RAR-related orphan receptor alpha and with the thyroid hormone receptor, respectively. Site-directed mutagenesis indicates that all four hydrophobic motifs are required for VDR transrepression by Hr. Point mutation of rat Hr at conserved residues corresponding to natural mutants causing alopecia in mice (G985W and a C-terminal deletion DeltaAK) and in humans (P95S, C422Y, E611G, R640Q, C642G, N988S, D1030N, A1040T, V1074M, and V1154D), as well as alteration of residues in the C-terminal Jumonji C domain implicated in histone demethylation activity (C1025G/E1027G and H1143G) revealed that all Hr mutants retained VDR association, and that transrepressor activity was selectively abrogated in C642G, G985W, N988S, D1030N, V1074M, H1143G, and V1154D. Four of these latter Hr mutants (C642G, N988S, D1030N, and V1154D) were found to associate normally with histone deacetylase-3. Finally, we identified three regions of human VDR necessary for association with Hr, namely residues 109-111, 134-201, and 202-303. It is concluded that Hr and VDR interact via multiple protein-protein interfaces, with Hr recruiting histone deacetylases and possibly itself catalyzing histone demethylation to effect chromatin remodeling and repress the transcription of VDR target genes that control the hair cycle.
MeSH term(s)	Alopecia/genetics ; Alopecia/metabolism ; Animals ; Conserved Sequence ; Hair/physiology ; Histone Deacetylases/metabolism ; Humans ; Immunoprecipitation ; Mutagenesis, Site-Directed ; Mutation ; Rats ; Receptors, Calcitriol/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	HR protein, human ; Receptors, Calcitriol ; Transcription Factors ; hr protein, rat ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2010-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.22578
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Zs.A 1114: Show issues

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Article ; Online: Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer.

Cron, Kyle R / Zhu, Kaya / Kushwaha, Deepa S / Hsieh, Grace / Merzon, Dmitry / Rameseder, Jonathan / Chen, Clark C / D'Andrea, Alan D / Kozono, David

PloS one

2013 Volume 8, Issue 9, Page(s) e73710

Abstract: Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi ...

Abstract	Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80-90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.
MeSH term(s)	Animals ; BRCA1 Protein/genetics ; Boronic Acids/pharmacology ; Bortezomib ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Carcinoma, Non-Small-Cell Lung/therapy ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Cell Survival/radiation effects ; Combined Modality Therapy ; DNA Repair/genetics ; Fanconi Anemia Complementation Group D2 Protein/genetics ; Female ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Lung Neoplasms/therapy ; Mice ; Mice, Nude ; NF-kappa B/genetics ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/pharmacology ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Pyrazines/pharmacology ; RNA Interference ; Rad51 Recombinase/genetics ; Radiation, Ionizing ; Radiation-Sensitizing Agents/pharmacology ; Radiotherapy/methods ; Reverse Transcriptase Polymerase Chain Reaction ; Xenograft Model Antitumor Assays
Chemical Substances	BRCA1 Protein ; Boronic Acids ; Fanconi Anemia Complementation Group D2 Protein ; NF-kappa B ; Proteasome Inhibitors ; Protein Subunits ; Pyrazines ; Radiation-Sensitizing Agents ; Bortezomib (69G8BD63PP) ; Rad51 Recombinase (EC 2.7.7.-) ; PSMA1 protein, human (EC 3.4.25.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2013-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0073710
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Article ; Online: Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells.

Mistry, Helena / Hsieh, Grace / Buhrlage, Sara J / Huang, Min / Park, Eunmi / Cuny, Gregory D / Galinsky, Ilene / Stone, Richard M / Gray, Nathanael S / D'Andrea, Alan D / Parmar, Kalindi

Molecular cancer therapeutics

2013 Volume 12, Issue 12, Page(s) 2651–2662

Abstract: Inhibitor of DNA binding 1 (ID1) transcription factor is essential for the proliferation and progression of many cancer types, including leukemia. However, the ID1 protein has not yet been therapeutically targeted in leukemia. ID1 is normally ... ...

Abstract	Inhibitor of DNA binding 1 (ID1) transcription factor is essential for the proliferation and progression of many cancer types, including leukemia. However, the ID1 protein has not yet been therapeutically targeted in leukemia. ID1 is normally polyubiquitinated and degraded by the proteasome. Recently, it has been shown that USP1, a ubiquitin-specific protease, deubiquitinates ID1 and rescues it from proteasome degradation. Inhibition of USP1 therefore offers a new avenue to target ID1 in cancer. Here, using a ubiquitin-rhodamine-based high-throughput screening, we identified small-molecule inhibitors of USP1 and investigated their therapeutic potential for leukemia. These inhibitors blocked the deubiquitinating enzyme activity of USP1 in vitro in a dose-dependent manner with an IC50 in the high nanomolar range. USP1 inhibitors promoted the degradation of ID1 and, concurrently, inhibited the growth of leukemic cell lines in a dose-dependent manner. A known USP1 inhibitor, pimozide, also promoted ID1 degradation and inhibited growth of leukemic cells. In addition, the growth of primary acute myelogenous leukemia (AML) patient-derived leukemic cells was inhibited by a USP1 inhibitor. Collectively, these results indicate that the novel small-molecule inhibitors of USP1 promote ID1 degradation and are cytotoxic to leukemic cells. The identification of USP1 inhibitors therefore opens up a new approach for leukemia therapy.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Arabidopsis Proteins/antagonists & inhibitors ; Arabidopsis Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Activation/drug effects ; Fanconi Anemia Complementation Group D2 Protein/metabolism ; High-Throughput Screening Assays ; Homologous Recombination/drug effects ; Humans ; Inhibitor of Differentiation Protein 1/metabolism ; Inhibitory Concentration 50 ; Leukemia/genetics ; Leukemia/metabolism ; Mice ; Pimozide/pharmacology ; Protease Inhibitors/chemistry ; Protease Inhibitors/metabolism ; Protease Inhibitors/pharmacology ; Protein Binding ; Proteolysis/drug effects ; Ubiquitin-Specific Proteases/antagonists & inhibitors ; Ubiquitin-Specific Proteases/metabolism ; Ubiquitination/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Arabidopsis Proteins ; Fanconi Anemia Complementation Group D2 Protein ; Inhibitor of Differentiation Protein 1 ; Protease Inhibitors ; Pimozide (1HIZ4DL86F) ; USP1 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12)
Language	English
Publishing date	2013-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-13-0103-T
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Zs.A 5750: Show issues

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Article: 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism.

Barthel, Thomas K / Mathern, Douglas R / Whitfield, G Kerr / Haussler, Carol A / Hopper, H Andrew / Hsieh, Jui-Cheng / Slater, Stephanie A / Hsieh, Grace / Kaczmarska, Magdalena / Jurutka, Peter W / Kolek, Olga I / Ghishan, Fayez K / Haussler, Mark R

The Journal of steroid biochemistry and molecular biology

2007 Volume 103, Issue 3-5, Page(s) 381–388

Abstract: 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, ... ...

Abstract	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 strongly upregulates FGF23 in bone. FGF23 then represses 1alpha-OHase activity in kidney, thus preventing spiraling induction of FGF23 by 1,25D. We also report that LRP5, Runx2, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic, are transcriptionally regulated by 1,25D. This coordinated regulation together with that of FGF23 and PTH allows 1,25D to play a central role in maintaining calcium and phosphate homeostasis and bone metabolism. In the cases of LRP5, Runx2, TRPV6, and Npt2c we show that transcriptional regulation results at least in part from direct binding of VDR near the relevant gene promoter. Finally, because 1,25D induces FGF23, and FGF23 in turn represses 1,25D synthesis, a reciprocal relationship is established with FGF23 indirectly curtailing 1,25D-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate. This newly revealed FGF23/1,25D/Pi axis is comparable in significance to phosphate and bone metabolism as the PTH/1,25D/Ca axis is to calcium homeostasis.
MeSH term(s)	Animals ; Base Sequence ; Bone and Bones/cytology ; Bone and Bones/metabolism ; Calcium/metabolism ; Cell Differentiation ; Cell Line ; Chromatin Immunoprecipitation ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism ; Gene Expression Regulation ; Homeostasis ; Humans ; Mice ; Minerals/metabolism ; Phosphorus/metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; RNA, Messenger/genetics ; Rats ; Receptors, Calcitriol/metabolism ; Transcription, Genetic/genetics ; Vitamin D/analogs & derivatives ; Vitamin D/metabolism
Chemical Substances	Fgf23 protein, rat ; Minerals ; RNA, Messenger ; Receptors, Calcitriol ; dihydroxy-vitamin D3 ; Vitamin D (1406-16-2) ; Phosphorus (27YLU75U4W) ; Fibroblast Growth Factors (62031-54-3) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2007-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1049188-0
ISSN	1879-1220 ; 0960-0760
ISSN (online)	1879-1220
ISSN	0960-0760
DOI	10.1016/j.jsbmb.2006.12.054
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Article: Cloning of a functional vitamin D receptor from the lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth.

Whitfield, G Kerr / Dang, Hope T L / Schluter, Samuel F / Bernstein, Ralph M / Bunag, Tara / Manzon, Lori A / Hsieh, Grace / Dominguez, Carlos Encinas / Youson, John H / Haussler, Mark R / Marchalonis, John J

Endocrinology

2003 Volume 144, Issue 6, Page(s) 2704–2716

Abstract: 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 ... ...

Abstract	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 of VDR from Petromyzon marinus, an unexpected finding because lampreys lack mineralized tissues and hair. Lamprey VDR (lampVDR) clones were obtained via RT-PCR from larval protospleen tissue and skin and mouth of juveniles. LampVDR expressed in transfected mammalian COS-7 cells bound 1,25-dihydroxyvitamin D(3) with high affinity, and transactivated a reporter gene linked to a vitamin D-responsive element from the human CYP3A4 gene, which encodes a P450 enzyme involved in xenobiotic detoxification. In tests with other vitamin D responsive elements, such as that from the rat osteocalcin gene, lampVDR showed little or no activity. Phylogenetic comparisons with nuclear receptors from other vertebrates revealed that lampVDR is a basal member of the VDR grouping, also closely related to the pregnane X receptors and constitutive androstane receptors. We propose that, in this evolutionarily ancient vertebrate, VDR may function in part, like pregnane X receptors and constitutive androstane receptors, to induce P450 enzymes for xenobiotic detoxification.
MeSH term(s)	Age Factors ; Amino Acid Sequence ; Animals ; Base Sequence ; Calcification, Physiologic ; Calcitriol/metabolism ; Cartilage ; Cloning, Molecular ; Cytochrome P-450 Enzyme System/genetics ; Evolution, Molecular ; Gene Expression ; Humans ; Lampreys/genetics ; Lampreys/growth & development ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary ; Receptors, Calcitriol/chemistry ; Receptors, Calcitriol/genetics ; Receptors, Calcitriol/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Tooth ; Transcription, Genetic ; Vertebrates
Chemical Substances	Receptors, Calcitriol ; Receptors, Cytoplasmic and Nuclear ; Cytochrome P-450 Enzyme System (9035-51-2) ; Calcitriol (FXC9231JVH)
Language	English
Publishing date	2003-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2002-221101
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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito