Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Full-length cDNAs of placental protein 20 (PP20) were cloned by screening a human placental cDNA library, which encode a 243 amino acid protein, identical to human thiamin pyrophosphokinase (hTPK) as confirmed by protein sequence analysis. Genomic alignment showed that the PP20/hTPK gene contains 9 exons. It is abundantly expressed in placenta, as numerous EST clones were identified. As thiamine metabolism deficiencies have been seen in placental infarcts previously, these indicate that PP20/hTPK may have a role in placental diseases. Analysis of the 1kb promoter region showed numerous putative transcription factor binding sites, which might be responsible for the ubiquitous PP20/hTPK expression. This may also be in accordance with the presence of the protein in tissues responsible for the regulation of the exquisite balance between cell division, differentiation and survival. TPK activity of the purified and recombinant protein was proved by mass spectrometry with electrospray ionization. By Western blot, PP20/hTPK was found in all human normal and tumorous adult and fetal tissues in nearly equal amounts, but not in sera. By immunohistochemical and immunofluorescent confocal imaging methods, diffuse labelling in the cytoplasm of the syncytiotrophoblasts and weak staining of the trophoblasts were observed, and the amount of PP20/hTPK decreased from the first trimester to the end of gestation. A 3D model of PP20/hTPK was computed (PDB No.: 1OLY) by homology modelling. A high degree of structural homology showed that the thiamin binding site was highly similar to that of the mouse enzyme, but highly different from the bacterial ones. Comparison of the catalytic centre sequences revealed differences, raising the possibility of designing new drugs which specifically inhibit bacterial and fungal enzymes without affecting PP20/hTPK and offering the possibility for safe antimicrobial therapy during pregnancy.
Placenta 2005 Jan
PMID:Cloning, sequencing, structural and molecular biological characterization of placental protein 20 (PP20)/human thiamin pyrophosphokinase (hTPK). 1566 9

The function of glycogen in the placenta remains controversial. Whether it is used as a source of fuel for placental consumption or by the fetus in times of need has yet to be determined. Two imprinted genes, insulin-like growth factor 2 (Igf2) and H19 are highly expressed in the placenta. We have previously demonstrated that mice with Igf2 deficiency have lower levels of placental glycogen. In this study, we used mice with targeted disruption of the H19 gene (H19(-/-)) to determine the importance of Igf2 over-expression in placental growth and glycogen stores. In addition, since Igf2 mediates most of its functions by signaling through the insulin and/or IGF Type 1 receptors, we determined whether gene deletions to these receptors could affect placental glycogen stores. Our data demonstrate that placentas from H19(-/-) mice are heavier, have higher number of glycogen cells, and contain larger glycogen concentrations than those of H19(+/+) mice. No differences in GSK-3, ERK, or total Akt expression or phosphorylation were found between genotypes; however, Akt1 protein expression levels were significantly increased in H19(-/-) placentas. Results obtained from insulin receptor or IGF Type 1 receptor mutant mice did not show differences in placental glycogen content compared to their wild-type littermates, supporting the notion of a specific placental Igf2 receptor. Taken together, these results support a role for Igf2 and Akt1, but not the insulin nor the IGF Type 1 receptors, in the regulation of placental growth and glycogen metabolism.
Placenta 2009 Aug
PMID:Placental glycogen stores are increased in mice with H19 null mutations but not in those with insulin or IGF type 1 receptor mutations. 1952 95

StarD7 gene encodes a protein that belongs to the StAR-related lipid transfer proteins involved in intracellular transport and metabolism of lipids. It has been previously documented that StarD7 has a wide-spread mRNA expression in trophoblastic tissues and several tumour cell lines with highest levels in both choriocarcinoma JEG-3 and JAR cells, hepatocellular carcinoma HepG2, and colorectal adenocarcinoma HT-29 cells. To understand the molecular mechanisms that regulate the expression of the human StarD7 gene, we have cloned and characterized the 5'-flanking region of the gene. Transient transfections of several 5'deleted StarD7-promoter-firefly luciferase constructs into JEG-3 cells indicated that the -312/+157 region contains the gene minimal promoter. In addition, sequence analysis of a 1.6kb gene fragment revealed the presence of a TATA-less promoter as well as multiple regulatory motifs, including one regulatory element corresponding to the T-cell factor 4 (TCF4) binding site. Inhibition of glycogen synthase kinase-3beta (GSK3beta), a component of Wnt/beta-catenin signalling, increased both StarD7 mRNA and protein expression as well as its promoter activity. Co-transfection experiments in JEG-3 cell line revealed that the StarD7 promoter is activated by TCF4 transcription factor and by its beta-catenin coactivator. Moreover, site-directed mutagenesis of the TCF4 site located -614/-608bp relative to the transcription start site markedly diminished StarD7 promoter activity. Chromatin immunoprecipitation analysis demonstrated that beta-catenin and TCF4 are bound in vivo to the StarD7 gene promoter in JEG-3 cells treated with lithium chloride. Collectively, these studies show that beta-catenin and TCF4 activate the human StarD7 gene interacting with its promoter region through Wnt/beta-catenin signalling.
Placenta 2009 Oct
PMID:Activation of beta-catenin signalling increases StarD7 gene expression in JEG-3 cells. 1967 47

The mechanisms by which maternal nutrient restriction (MNR) causes reduced fetal growth are poorly understood. We hypothesized that MNR inhibits placental mechanistic target of rapamycin (mTOR) and insulin/IGF-I signaling, down-regulates placental nutrient transporters, and decreases fetal amino acid levels. Pregnant baboons were fed control (ad libitum, n=11) or an MNR diet (70% of controls, n=11) from gestational day (GD) 30. Placenta and umbilical blood were collected at GD 165. Western blot was used to determine the phosphorylation of proteins in the mTOR, insulin/IGF-I, ERK1/2, and GSK-3 signaling pathways in placental homogenates and expression of glucose transporter 1 (GLUT-1), taurine transporter (TAUT), sodium-dependent neutral amino acid transporter (SNAT), and large neutral amino acid transporter (LAT) isoforms in syncytiotrophoblast microvillous membranes (MVMs). MNR reduced fetal weights by 13%, lowered fetal plasma concentrations of essential amino acids, and decreased the phosphorylation of placental S6K, S6 ribosomal protein, 4E-BP1, IRS-1, Akt, ERK-1/2, and GSK-3. MVM protein expression of GLUT-1, TAUT, SNAT-2 and LAT-1/2 was reduced in MNR. This is the first study in primates exploring placental responses to maternal undernutrition. Inhibition of placental mTOR and insulin/IGF-I signaling resulting in down-regulation of placental nutrient transporters may link maternal undernutrition to restricted fetal growth.
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PMID:Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon. 2433 3