Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00790 (PGA)
 2,475 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclopentenone PGs (PGA and PGJ series) inhibit tumor cell proliferation in vitro and tumorigenesis in vivo via mechanisms that are at present poorly understood. The C6 rat glioma cell line synthesizes and secretes insulin-like growth factor-I (IGF-I), which is believed to act as an autocrine factor for these cells. PGA2 inhibits the proliferation of the C6 cells and causes an increase in the fraction of cells in the G1 phase of the cell cycle. The inhibition of cell proliferation by PGA2 is accompanied by a decrease in the abundance of IGF-I messenger RNA (mRNA). This regulation of IGF-I gene expression is specific, as the abundance of hypoxanthine-guanine phosphoribosyl transferase (HPRT) and ubiquitin mRNA is not significantly affected by PGA2. The repression of IGF-I gene expression is observed at PGA2 concentrations as low as 10 microM and is evident within 4 h after treatment of the C6 cells with PGA2. In addition to specifically regulating the expression of the IGF-I gene, PGA2 also decreases the abundance of cyclin D1 mRNA and increases the abundance of Waf1 mRNA. The inhibition of cell proliferation by PGA2 is partially reversed by coaddition of IGF-I, indicating partial dominance of IGF-I action over PGA2 action. To investigate the molecular basis for the regulation of IGF-I gene expression by PGA2, we developed a sensitive RT-PCR assay for IGF-I nuclear transcripts. A similar assay was developed for quantifying HPRT transcripts, which were used as a control. Treatment of the C6 cells with 20 microM PGA2 resulted in approximately a 6-fold decrease in IGF-I mRNA and IGF-I nuclear transcripts. In contrast, HPRT mRNA and nuclear transcript levels were not significantly affected by PGA2. These results indicate that the decrease in IGF-I mRNA abundance that occurs in response to PGA2 is caused largely by a decrease in IGF-I nuclear transcript levels. To identify the cis-acting element that mediates the effect of PGA2 on IGF-I transcription, C6 cells were transiently transfected with IGF-I/luciferase expression constructs in which luciferase transcription is driven by IGF-I P1 promoter fragments extending from -1711 to -328 or from -1114 to +328 relative to the beginning of exon 1. Treatment of cells with PGA2 in these transient transfection assays did not decrease luciferase activity. These results suggest that the cis-acting regulatory element required for the response to PGA2 is located outside the -1711 to +328 promoter interval.
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PMID:Prostaglandin A2 specifically represses insulin-like growth factor-I gene expression in C6 rat glioma cells. 904 99

The molecular pathways by which the cyclopentenone prostaglandins (PGA and PGJ series) inhibit cell growth and tumorigenicity are poorly understood. These cellular responses may be caused by specific regulation of growth-related and stress-induced genes. A variety of prostaglandins were tested for their ability to regulate insulin-like growth factor-I (IGF-I) and Waf1 gene expression in C6 rat glioma cells. The prostaglandins (in order of potency) PGJ2 > PGA1 > PGA2, approximately PGD2 >> PGE2 all significantly repressed IGF-I gene expression. With the exception of PGE2, the same prostaglandins that repressed IGF-I also induced Waf1 gene expression. However, the order of potency for Waf1 induction was different than for IGF-I repression: PGA2 > PGA1 approximately PGJ2 > PGD2. The different order of potency of the prostaglandins in regulating IGF-I and Waf1 gene expression suggests that different intracellular signals may be involved in regulating the two genes. Augmentation of glutathione levels by pretreatment of cells with N-acetyl-L-cysteine attenuated the effect of PGA2 on IGF-I and Waf1 gene expression. conversely, depletion of the intracellular glutathione pool by pretreatment with buthionine sulfoximine potentiated the effect of PGA2 on the expression of both genes. These results suggest that conjugation with glutathione prevents the regulation of gene expression by PGA2. We also tested the effect of several simpler compounds that contain a five-membered ring system on IGF-I and Waf1 gene expression. 2-Cyclopenten-1-one, but not cyclopentene or cyclopentene, repressed IGF-I and induced Waf1 gene expression, demonstrating the requirement for an alpha, beta-unsaturated carbonyl for regulation of the two genes. The dione compound 4-cyclopentene-1,3-dione, which has two potentially reactive carbons rather than one, was considerably more potent than 2-cyclopentene-1-one in repressing IGF-I gene expression (IC50 = 30 microM for 4-cyclopentene-1,3-dione as compared with 167 microM for 2-cyclopentene-1-one). Additional results indicated that diethyl maleate, which has two alpha,beta-unsaturated carbonyls in a non-cyclic configuration, also repressed IGF-I gene expression (IC50 = 214 microM) and induced Waf1 gene expression, indicating that the cyclic structure is not required for either effect.
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PMID:Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-I and Waf1 gene expression. 954 24

Arguably one of the most complex joints in the body, the temporomandibular joint (TMJ) presents one of the most difficult problems in modem medicine. Tissue engineering, for the TMJ disc in particular, has been proposed as a potential breakthrough treatment strategy for TMJ disorders. Central to tissue engineering is understanding growth factor effects on TMJ disc cells, and to the best of our knowledge, this is the first 3D growth factor study for these cells. The purpose was to examine the effects of high and low concentrations of basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF), and transforming growth factor-beta1 (TGF-beta) on porcine TMJ disc cells. Cells were seeded onto non-woven PGA scaffolds (95% porosity) in spinner flasks, then cultured with a growth factor for 6 weeks. Constructs were analyzed for mechanical and structural integrity, cell number, and matrix biosynthesis. All growth factors improved mechanical and structural integrity compared to the control. IGF and TGF-beta were most effective at promoting collagen synthesis, although there were no significant differences in glycosaminoglycan synthesis or cell number between any groups. After considering the economic advantage of IGF over TGF-beta, the conclusion of this study is to use IGF in future TMJ disc tissue engineering experiments.
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PMID:Evaluation of three growth factors for TMJ disc tissue engineering. 1586 29