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17 beta-hydroxysteroid dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin.

https://arctichealth.org/en/permalink/ahliterature24541
Source
Cancer Res. 1992 Jan 15;52(2):290-4
Publication Type
Article
Date
Jan-15-1992
Author
M. Poutanen
B. Moncharmont
R. Vihko
Author Affiliation
Department of Clinical Chemistry, University of Oulu, Finland.
Source
Cancer Res. 1992 Jan 15;52(2):290-4
Date
Jan-15-1992
Language
English
Publication Type
Article
Keywords
17-Hydroxysteroid Dehydrogenases - genetics - metabolism
Breast Neoplasms - enzymology - genetics
Gene Expression Regulation, Neoplastic - drug effects
Humans
Isoenzymes - genetics
Placenta - enzymology
Pregnenediones - pharmacology
Progesterone Congeners - pharmacology
RNA, Messenger - genetics
RNA, Neoplasm - genetics
Receptors, Estrogen - metabolism
Receptors, Progesterone - metabolism
Research Support, Non-U.S. Gov't
Tumor Cells, Cultured
Abstract
The expression of the 17 beta-hydroxysteroid dehydrogenase (17-HSD) gene in a series of human breast cancer cell lines was studied by Northern blot hybridization with a cDNA probe and by a time-resolved immunofluorometric assay using polyclonal antibodies against the enzyme protein. The 17-HSD enzyme protein concentration was measured in the 800 x g cell extract. A high concentration was measured in the BT-20 cell line, corresponding to one-fourth of the average concentration in placental tissue. Western blot analysis indicated that the antigen corresponded to a single Mr 35,000 band. In 2 other cell lines (MDA-MB-361 and T-47D), the 17-HSD protein concentration was much lower, but still measurable, whereas in the remaining 5 cell lines (HBL-100, MCF-7, MDA-MB-231, MDA-MB-468, and ZR-75-1) it was below the detection limit of the assay. Treatment of the cells for 5 days with the synthetic progestin, ORG2058, resulted in an increase of the 17-HSD protein concentration only in the T-47D cell line. By Northern blot analysis, a low level of 2.3-kilobase mRNA transcripts was detected in all 8 cell lines. In addition, a 1.3-kilobase 17-HSD mRNA was present in the samples from the 3 cell lines containing measurable amounts of 17-HSD protein in the cell extract, and the band intensities were proportional to the amount of protein measured with the immunofluorometric assay. Only in the T-47D cell line did progestin treatment correspond to an increased amount of the 17-HSD 1.3-kilobase mRNA. These results suggest that the 1.3-kilobase mRNA for 17-HSD is the form most closely associated with protein expression and is also the only form responding to the progestin induction of the 17-HSD gene.
PubMed ID
1728403 View in PubMed
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17 beta-hydroxysteroid dehydrogenases--their role in pathophysiology.

https://arctichealth.org/en/permalink/ahliterature17852
Source
Mol Cell Endocrinol. 2004 Feb 27;215(1-2):83-8
Publication Type
Article
Date
Feb-27-2004
Author
P. Vihko
P. Härkönen
P. Soronen
S. Törn
A. Herrala
R. Kurkela
A. Pulkka
O. Oduwole
V. Isomaa
Author Affiliation
Biocenter Oulu and Research Center for Molecular Endocrinology, University of Oulu, P.O. Box 5000, FIN-90014, Oulu, Finland. pvihko@whoccr.oulu.fi
Source
Mol Cell Endocrinol. 2004 Feb 27;215(1-2):83-8
Date
Feb-27-2004
Language
English
Publication Type
Article
Keywords
17-Hydroxysteroid Dehydrogenases - metabolism
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gonadal Steroid Hormones - metabolism
Humans
Neoplasms - enzymology
Oxygen - metabolism
Research Support, Non-U.S. Gov't
Abstract
17 beta-Hydroxysteroid dehydrogenases (17HSDs) regulate the biological activity of sex steroid hormones in a variety of tissues by catalyzing the interconversions between highly active steroid hormones, e.g. estradiol and testosterone, and corresponding less active hormones, estrone and androstenedione. Epidemiological and endocrine evidence indicates that estrogens play a role in the etiology of breast cancer, while androgens are involved in mechanisms controlling the growth of normal and malignant prostatic cells. Using LNCaP prostate cancer cell lines, we have developed a cell model to study the progression of prostate cancer. In the model LNCaP cells are transformed in culture condition into more aggressive cells. Our data suggest that substantial changes in androgen and estrogen metabolism occur in the cells, leading to increased production of active estrogens during the process. In breast cancer, the reductive 17HSD type 1 activity is predominant in malignant cells, while the oxidative 17HSD type 2 mainly seems to be present in non-malignant breast epithelial cells. Deprivation of an estrogen response by using specific 17HSD type 1 inhibitors is a tempting approach in treating estrogen-dependent breast cancer. Our recent studies demonstrate that in addition to sex hormone target tissues, estrogens may be important in the development of cancer in some other tissues previously not considered to be estrogen target tissues, such as the gastrointestinal tract.
PubMed ID
15026178 View in PubMed
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17Beta-hydroxysteroid dehydrogenase type 2: independent prognostic significance and evidence of estrogen protection in female patients with colon cancer.

https://arctichealth.org/en/permalink/ahliterature18039
Source
J Steroid Biochem Mol Biol. 2003 Nov;87(2-3):133-40
Publication Type
Article
Date
Nov-2003
Author
Olayiwola O Oduwole
Markus J Mäkinen
Veli V Isomaa
Anitta Pulkka
Petra Jernvall
Tuomo J Karttunen
Pirkko T Vihko
Author Affiliation
Biocenter Oulu, Research Center for Molecular Endocrinology, WHO Collaborating Centre for Research on Reproductive Health, P.O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland.
Source
J Steroid Biochem Mol Biol. 2003 Nov;87(2-3):133-40
Date
Nov-2003
Language
English
Publication Type
Article
Keywords
17-Hydroxysteroid Dehydrogenases - genetics - metabolism
Adult
Aged
Aged, 80 and over
Colonic Neoplasms - enzymology - genetics - pathology
Comparative Study
Estrogens - metabolism
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Isoenzymes - metabolism
Male
Middle Aged
Neoplasm Staging
Prognosis
Proportional Hazards Models
RNA, Messenger - biosynthesis - genetics
Research Support, Non-U.S. Gov't
Sex Factors
Survival Rate
Abstract
The mRNA expression of 17beta-hydroxysteroid dehydrogenase (17HSD) types 1 and 2 enzymes catalyzing opposite reaction of estrogen metabolism was investigated in colon cancer. Further, the significance of the 17HSD type 2 enzyme as a possible marker of colorectal cancer (CRC) prognosis was studied. In the normal mucosa, 17HSD type 2 mRNA was predominantly expressed in the surface epithelium and in the upper parts of the crypts. In the lamina propria expression was seen in endothelial cells and mononuclear phagocytes. In colorectal tumors, 17HSD type 2 expression was in most cases downregulated. Female patients had significantly more cancers with high 17HSD type 2 mRNA expression (n=11/35; 31%) than male patients (n=3/39; 8%) (P=0.02). We observed a significant impact of 17HSD type 2 mRNA expression on survival in female patients with distal colorectal cancer (n=24), with an overall cumulative 5-year survival rate of 54% in those with low 17HSD type 2 mRNA expression. None of the female patients with high 17HSD type 2 mRNA expression survived (n=11; P=0.0068; log rank 7.32). In male patients, no significant association with survival was observed. Our data provide evidence suggesting that low 17HSD type 2 mRNA expression is an independent marker of favorable prognosis in females with distal colorectal cancer, supporting the presence of gender- and location-related differences in the pathogenesis of colon cancer.
PubMed ID
14672733 View in PubMed
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164Ile allele in the beta2-Adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study.

https://arctichealth.org/en/permalink/ahliterature173671
Source
Pharmacogenet Genomics. 2005 Sep;15(9):633-45
Publication Type
Article
Date
Sep-2005
Author
Amar A Sethi
Anne Tybjaerg-Hansen
Gorm B Jensen
Børge G Nordestgaard
Author Affiliation
Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark.
Source
Pharmacogenet Genomics. 2005 Sep;15(9):633-45
Date
Sep-2005
Language
English
Publication Type
Article
Keywords
Alleles
Arginine - chemistry
Blood pressure
Body mass index
Denmark
Female
Gene Expression Regulation
Gene Frequency
Genetic Variation
Genotype
Glutamic Acid - chemistry
Glutamine - chemistry
Glycine - chemistry
Haplotypes
Heart rate
Heterozygote
Humans
Hypertension - genetics
Isoleucine - chemistry
Linkage Disequilibrium
Male
Receptors, Adrenergic, beta-2 - genetics
Risk
Risk factors
Sequence Analysis, DNA
Sex Factors
Time Factors
Abstract
Since beta2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor gene associated with elevated blood pressure.
We genotyped 9185 individuals from the adult Danish general population.
Allele frequencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively. Among women never treated with antihypertensive medication those heterozygous for Thr164Ile versus non-carriers had increased diastolic blood pressure (P=0.02). Women heterozygous for Thr164Ile versus non-carriers had an odds ratio for elevated blood pressure of 1.93 (95% CI: 1.30-2.86). Finally, women double heterozygous for Thr164Ile and Gln27Glu or Gly16Arg versus non-carriers at all 3 loci had an odds ratio for elevated blood pressure of 2.49 (1.28-4.85) or 3.19 (1.46-6.97). In men, blood pressure was not influenced by this genetic variation.
In women Thr164Ile heterozygosity is associated with increased diastolic blood pressure, and represent a risk factor for elevated blood pressure in women in the general population. This was most pronounced in those women also heterozygous for Gln27Glu or Gly16Arg.
PubMed ID
16041242 View in PubMed
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677 C-->T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia.

https://arctichealth.org/en/permalink/ahliterature197794
Source
Obstet Gynecol. 2000 Aug;96(2):277-80
Publication Type
Article
Date
Aug-2000
Author
H. Laivuori
R. Kaaja
O. Ylikorkala
T. Hiltunen
K. Kontula
Author Affiliation
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. hannele.laivuori@pp.fimnet.fi
Source
Obstet Gynecol. 2000 Aug;96(2):277-80
Date
Aug-2000
Language
English
Publication Type
Article
Keywords
Adult
Alleles
Amino Acid Substitution
Case-Control Studies
DNA Primers
Female
Finland
Gene Expression Regulation, Enzymologic
Gene Frequency
Genotype
Heterozygote
Humans
Methylenetetrahydrofolate Reductase (NADPH2)
Oxidoreductases Acting on CH-NH Group Donors - genetics
Polymerase Chain Reaction
Polymorphism, Genetic
Pre-Eclampsia - enzymology - genetics
Pregnancy
Abstract
To evaluate C to T substitution at nucleotide 677 of N(5), N(10)-methylenetetrahydrofolate reductase gene in women with prior preeclamptic or normotensive pregnancies.
Methylenetetrahydrofolate reductase genotypes were determined in 113 Finnish women with preeclamptic first pregnancies and 103 controls with one or more normotensive pregnancies, using polymerase chain reaction and restriction enzyme analysis. Preeclampsia was defined as severe in 100 women who fulfilled one or more of the subsequent criteria: systolic blood pressure (BP) at least 160 mmHg, diastolic BP at least 110 mmHg, or proteinuria at least 2 g per 24-hour urine collection.
There were no significant differences in prevalences of the methylenetetrahydrofolate reductase genotypes (CC, CT, and TT) between groups (57%, 40%, and 3% in the preeclamptic group and 54%, 39%, and 7%, respectively, in controls). The frequency of the T677 allele was 0.23 in the preeclamptic group and 0.26 in the control group (difference 0.03; 95% confidence interval -0.08, 0.14; P =.51). Our sample had 60% power to detect a difference of the allele frequencies similar to that (0.12) reported previously. The result was similar when analysis was restricted to patients with severe preeclampsia (T677 allele frequency 0.22).
A carrier status for the T677 allele of the methylenetetrahydrofolate reductase gene does not predispose to preeclampsia, at least in the Finnish population.
PubMed ID
10908777 View in PubMed
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Aberrant expression of E-cadherin and beta-catenin in association with transforming growth factor-beta1 in urinary bladder lesions in humans after the Chernobyl accident.

https://arctichealth.org/en/permalink/ahliterature16573
Source
Cancer Sci. 2006 Jan;97(1):45-50
Publication Type
Article
Date
Jan-2006
Author
Alina Romanenko
Keiichirou Morimura
Anna Kinoshita
Hideki Wanibuchi
Alexander Vozianov
Shoji Fukushima
Author Affiliation
Department of Pathology, Institute of Urology, Academy of Medical Sciences of Ukraine, 9a, Yu. Kotzubinsky Street, 04053, Kiev, Ukraine.
Source
Cancer Sci. 2006 Jan;97(1):45-50
Date
Jan-2006
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Adult
Aged
Aged, 80 and over
Bladder Neoplasms - metabolism - pathology
Cadherins - metabolism
Chernobyl Nuclear Accident
Female
Gene Expression Regulation
Humans
Immunohistochemistry
Male
Middle Aged
Research Support, Non-U.S. Gov't
Transforming Growth Factor beta - metabolism
beta Catenin - metabolism
Abstract
This study examines the molecular pathways of cell-cell communication in chronic inflammatory processes associated with long-term low-dose urinary bladder exposure to ionizing radiation in people without major disease living more than 19 years in radio-contaminated areas of Ukraine after the Chernobyl accident. Patterns of components of the E-cadherin/beta-catenin complex, and transforming growth factor-beta1 (TGF-beta1) and inducible nitric oxide synthase (iNOS) expression were immunohistochemically evaluated in urinary bladder biopsies from 52 males with benign prostate hyperplasia and 8 females with chronic cystitis (group 1). For comparison, 25 males and 6 females living in non-contaminated areas of Ukraine were also investigated (group 2). Fourteen patients with primary urothelial carcinomas, which were operated on before the Chernobyl accident, were included as a carcinoma group. Chronic proliferative atypical cystitis ('Chernobyl cystitis') was observed in group 1 patients. Foci of dysplasia and carcinoma in situ were found in 51 (85%) and 34 (57%) of the 60 cases, respectively. Chronic cystitis with areas of dysplasia was detected in only 4 (13%) cases of 31 group 2 patients. Statistically significant differences in immunohistochemical scores for TGF-beta1 in the urothelium and lamina propria, iNOS in the urothelium and both beta-catenin and E-cadherin in the cytoplasm were observed between groups 1 and 2 with marked expression in group 1. Furthermore, TGF-beta1 overexpression and alteration in E-cadherin/beta-catenin complexes in bladder urothelium might play a crucial role in urinary bladder carcinogenesis in humans exposed to long-term low-dose ionizing radiation.
PubMed ID
16367920 View in PubMed
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Aberrant expression of miR-218 and miR-204 in human mesial temporal lobe epilepsy and hippocampal sclerosis-convergence on axonal guidance.

https://arctichealth.org/en/permalink/ahliterature260948
Source
Epilepsia. 2014 Dec;55(12):2017-27
Publication Type
Article
Date
Dec-2014
Author
Sanne S Kaalund
Morten T Venø
Mads Bak
Rikke S Møller
Henning Laursen
Flemming Madsen
Helle Broholm
Bjørn Quistorff
Peter Uldall
Niels Tommerup
Sakari Kauppinen
Anne Sabers
Kees Fluiter
Lisbeth B Møller
Anne Y Nossent
Asli Silahtaroglu
Jørgen Kjems
Eleonora Aronica
Zeynep Tümer
Source
Epilepsia. 2014 Dec;55(12):2017-27
Date
Dec-2014
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Animals
Cohort Studies
Denmark
Embryo, Mammalian
Epilepsy, Temporal Lobe - complications - metabolism - pathology
Female
Gene Expression Profiling
Gene Expression Regulation - physiology
Glutamate Plasma Membrane Transport Proteins - genetics - metabolism
Hippocampus - metabolism
Humans
Male
MicroRNAs - metabolism
Middle Aged
Nerve Tissue Proteins - metabolism
Netherlands
Pyramidal Cells - metabolism - pathology
Receptors, Metabotropic Glutamate - metabolism
Reproducibility of Results
Sclerosis - etiology - pathology
Sequence Analysis, RNA
Swine
Young Adult
Abstract
Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS.
miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay.
miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204.
miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS.
PubMed ID
25410734 View in PubMed
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Aberrant expression of the human epidermal growth factor receptor 2 oncogene is not a common feature in osteosarcoma.

https://arctichealth.org/en/permalink/ahliterature101871
Source
Hum Pathol. 2011 Jun;42(6):859-66
Publication Type
Article
Date
Jun-2011
Author
Daniel Baumhoer
Jan Smida
Katja Specht
Karin Bink
Leticia Quintanilla-Martinez
Michael Rosemann
Heide Siggelkow
Walter B J Nathrath
Michael J Atkinson
Stefan Bielack
Gernot Jundt
Michaela Nathrath
Author Affiliation
Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland. dbaumhoer@mac.com
Source
Hum Pathol. 2011 Jun;42(6):859-66
Date
Jun-2011
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Bone Neoplasms - genetics - metabolism - pathology
Child
Child, Preschool
DNA, Neoplasm - analysis
Female
Gene Expression Regulation, Neoplastic - physiology
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Male
Middle Aged
Oligonucleotide Array Sequence Analysis
Osteosarcoma - genetics - metabolism - pathology
Polymorphism, Single Nucleotide
Prognosis
RNA, Messenger - metabolism
Receptor, erbB-2 - genetics - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Markers, Biological - genetics - metabolism
Young Adult
Abstract
Human epidermal growth factor receptor 2 expression in osteosarcoma and its relationship to prognosis have been the subject of several conflicting reports, most of them relying on immunohistochemical studies. Because the urgent need of prognostic markers and effective new treatment options for osteosarcoma patients, we evaluated the role of human epidermal growth factor receptor 2 in 2 well-characterized sets of pretherapeutic osteosarcoma samples (46 paraffin-embedded and 46 fresh-frozen biopsy samples) using immunohistochemistry with 2 different antibodies [DAKO A0485 (Glostrup, Denmark) and Novocastra CB11 (Newcastle, UK)] as well as fluorescence in situ hybridization, real-time polymerase chain reaction, and SNP array analyses and correlated our findings with clinicopathological parameters. However, our study failed to detect unequivocal evidence of human epidermal growth factor receptor 2 gene amplification or overexpression of human epidermal growth factor receptor 2 messenger RNA or protein in any of the investigated tumors. Only in a small subset of samples, a moderate increase in messenger RNA levels (13.6%) or focal membranous immunoreactivity (8.7%; A0485) was detected but did not correlate with survival or response to chemotherapy. Cytoplasmic staining was identified more frequently (63%; CB11) but again did not show any association with clinicopathological parameters. In conclusion, our study does not support a role for human epidermal growth factor receptor 2 as a prognostic marker in osteosarcoma.
PubMed ID
21292304 View in PubMed
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Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms.

https://arctichealth.org/en/permalink/ahliterature162439
Source
J Neurosci. 2007 Jul 18;27(29):7648-53
Publication Type
Article
Date
Jul-18-2007
Author
Marlen Knobloch
Mélissa Farinelli
Uwe Konietzko
Roger M Nitsch
Isabelle M Mansuy
Author Affiliation
Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland.
Source
J Neurosci. 2007 Jul 18;27(29):7648-53
Date
Jul-18-2007
Language
English
Publication Type
Article
Keywords
Age Factors
Amyloid Precursor Protein Secretases - genetics
Amyloid beta-Peptides - chemistry - metabolism - ultrastructure
Analysis of Variance
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases - genetics
Dose-Response Relationship, Radiation
Electric Stimulation - methods
Excitatory Postsynaptic Potentials - drug effects - physiology
Gene Expression Regulation - genetics
Hippocampus - cytology
Humans
Long-Term Potentiation - genetics - physiology - radiation effects
Mice
Mice, Transgenic
Microscopy, Electron, Transmission - methods
Neurons - drug effects - physiology
Patch-Clamp Techniques
Phosphoprotein Phosphatases - physiology
Presenilin-1 - genetics
Protein Phosphatase 1
Reverse Transcriptase Polymerase Chain Reaction - methods
Abstract
Amyloid beta (Abeta) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. The mechanisms underlying such toxicity on synaptic functions are complex and not fully understood. Here, we provide the first evidence that these mechanisms involve protein phosphatase 1 (PP1). Using a novel transgenic mouse model expressing human APP with the Swedish and Arctic mutations that render Abeta more prone to form oligomers (arcAbeta mice), we show that the LTP impairment induced by Abeta oligomers can be fully reversed by PP1 inhibition in vitro. We further demonstrate that the genetic inhibition of endogenous PP1 in vivo confers resistance to Abeta oligomer-mediated toxicity and preserves LTP. Overall, these results reveal that PP1 is a key player in the mechanisms of AD pathology.
PubMed ID
17634359 View in PubMed
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Abnormal regulation of the LDL-R and HMG CoA reductase genes in subjects with familial hypercholesterolemia with the "French Canadian mutation".

https://arctichealth.org/en/permalink/ahliterature211598
Source
Atherosclerosis. 1996 Jul;124(1):103-17
Publication Type
Article
Date
Jul-1996
Author
L. Yu
S. Qiu
J. Genest
Author Affiliation
Cardiovascular Genetics Laboratory, Clinical Research Institute of Montréal, Québec Canada.
Source
Atherosclerosis. 1996 Jul;124(1):103-17
Date
Jul-1996
Language
English
Publication Type
Article
Keywords
Anticholesteremic Agents - pharmacology - therapeutic use
Canada - epidemiology
Cells, Cultured
Enzyme Induction
Enzyme Inhibitors - pharmacology - therapeutic use
Ethnic Groups - genetics
Female
Fibroblasts - metabolism
France - ethnology
Gene Expression Regulation - drug effects
Haploidy
Humans
Hydroxymethylglutaryl CoA Reductases - genetics
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperlipoproteinemia Type II - drug therapy - ethnology - genetics
Lipoproteins, LDL - metabolism
Lovastatin - pharmacology - therapeutic use
Male
Prevalence
RNA, Messenger - biosynthesis - genetics
Receptors, LDL - genetics - metabolism
Sequence Deletion
Transcription, Genetic
Treatment Failure
Abstract
Familial hypercholesterolemia (FH) is seen with high frequency in the province of Québec, Canada. A large deletion (> 10 kb) of the 5'-end of the low density lipoprotein receptor (LDL-R) gene is the major mutation of the LDL-R in FH subjects in Québec (approximately 60% of FH subjects). No mRNA is produced from the allele bearing the mutation, and cellular cholesterol obtained by receptor-mediated endocytosis is under the control of the non-deletion allele. We have previously reported that some patients with the 10-kb deletion (approximately 9%) fail to respond to the hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) inhibitor class of medications. We studied mRNA levels of the LDL-R and HMG CoA reductase genes in response to the HMG CoA reductase inhibitor lovastatin in a time- and dose-dependent fashion in cultured human skin fibroblasts and we devised an in vitro model to study the response to drug therapy in subjects with FH. We determined mRNA levels by RNase protection assay in skin fibroblasts obtained from controls (n = 3) and FH subjects with the > 10-kb deletion (responders, n = 3; non responders, n = 3; to drug therapy). We measured 125I-LDL binding on skin fibroblasts grown in the presence of lipoprotein-deficient serum with or without 1 microM lovastatin, using 10 micrograms/mL of 125I-LDL protein. Control subjects exhibited coordinate regulation of the LDL-R and HMG CoA reductase genes in response to lovastatin, 0.1-25 microM, for 0-24 h. Correlation coefficients between mRNA levels of both genes were > 0.9 in controls and FH subjects. However, by linear regression analysis, the corresponding slopes for the correlation between both genes were 0.98 (controls), 3.36 and 3.63 (FH responders and non-responders), indicating a pattern of dissociated but still coordinate regulation in FH subjects. The magnitude of increase of mRNA levels of the LDL-R gene was approximately five-fold over LPDS in controls, two-fold in FH responders and two-fold in non-responders. Binding studies using 125I-LDL reveal that a control subject and all responders had a 2-2.5-fold increase in binding to cell surface receptors but two out of three FH non-responders showed no increase in binding in response to 1 microM lovastatin. The LDL-R and HMG CoA reductase genes are expressed in coordinate regulation in fibroblasts from subjects with FH due to the > 10-kb deletion, but with a proportionately greater up-regulation of the HMG CoA reductase gene. Some subjects, with FH caused by the > 10-kb deletion of the LDL-R gene, who fail to respond to HMG CoA reductase inhibitors have abnormal LDL receptor binding activity at the cell surface in response to lovastatin in vitro.
PubMed ID
8800498 View in PubMed
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598 records – page 1 of 60.