Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
 4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene transfer systems targeting the asialoglycoprotein receptor have been developed to introduce functional genes into cells in culture and livers of intact animals. A synthetic neoglycoprotein carrier was constructed and complexed to a chimeric gene containing the cDNA for human factor IX ligated to the promoter-regulatory region of the gene for phosphoenolpyruvate carboxykinase from the rat. The complex was used to transfect human hepatoma cells that express the asialoglycoprotein receptor. Human factor IX DNA sequences were found in cells 10 days after treatment. A 1.4 kB mRNA transcript was detected by Northern blot hybridization, which was inducible by treatment with dexamethasone or cAMP with theophylline. Western blot hybridization of proteins secreted into the culture medium detected human factor IX. The chimeric gene was also transferred into livers of rats using the neoglycoprotein carrier system after partial hepatectomy. Although the results were variable, the exogenous gene was transcribed in livers of several animals, and maximal levels of expression of the fully processed human factor IX were detected 30 days after introduction. The concentration of factor IX in the blood returned to control levels 60 days after transfection. Factor IX production was induced as late as 96 days after treatment by feeding transfected animals a diet high in protein but devoid of carbohydrates. This DNA carrier system can be used to introduce functional genes into the livers of rats, and may be a useful technique for gene therapy targeting the liver.
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PMID:Regulation of the phosphoenolpyruvate carboxykinase/human factor IX gene introduced into the livers of adult rats by receptor-mediated gene transfer. 837 Apr 79

HBC-3 hepatic stem cells maintained in the undifferentiated state can be induced to differentiate along the hepatocyte lineage in response to DMSO (Rogler, 1997). In order to understand the complex transcriptional regulatory mechanisms associated with the differentiation of these somatic stem cells and to identify novel candidate stem cell and differentiation associated genes, we have begun to characterize the transcriptome of HBC-3 cells during a 7-day differentiation protocol. This analysis showed that differentiating HBC-3 cells undergo biphasic bursts of gene regulation peaking at 3 hours and 120 hours of DMSO treatment. In the undifferentiated state, HBC-3 cells express muscle, neuron, myeloid, and lymphoid specific genes that are rapidly downregulated during hepatocytic differentiation. Cluster analysis has revealed large groups of genes with different temporal regulation profiles demonstrating complex and widespread transcriptional changes. Specifically, we discovered a multifaceted downregulation of the Wnt/beta-catenin pathway accompanied by the repression of TCF target genes during HBC-3 differentiation. In addition, there is downregulation of cellular receptors for fibronectin and laminin and other extracellular matrix molecules indicative of widespread cell surface alterations. DMSO induces cell cycle arrest, and this is reflected in upregulation of growth inhibitory proteins such as cyclin I and p18 and downregulation of cyclins B1 and D. Genes needed for hepatocytic functions, such as apolipoprotein C-IV, phosphoenolpyruvate carboxykinase, alcohol dehydrogenase, and asialoglycoprotein receptor were upregulated. Finally, transcriptional regulators including Twist, Snail, HNF1a, and GATA6 were upregulated during differentiation of HBC-3 cells. The significance of these findings is that our genome-based approach has allowed the parallel identification of multiple regulatory pathways that is needed to begin to fully understand the complex differentiation process.
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PMID:Genomic expression analysis implicates Wnt signaling pathway and extracellular matrix alterations in hepatic specification and differentiation of murine hepatic stem cells. 1177 78