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)

Cyclopentenone prostaglandins (PG) such as delta 12-PGJ2 and PGA are potent inhibitors of growth in a variety of cultured cells, including human epidermal cells. To clarify the mechanism of PG cytotoxicity in human epidermal cells, we examined the effects of delta 12-PGJ2 on the induction of a heat shock protein (HSP), and on the organization of cytoskeletons in the HSC-I-transformed human epidermal cell line. Immunoblot analysis using a monoclonal antibody specific for the 72-kD heat shock protein (HSP72) revealed that a 12-h incubation with 5 micrograms/ml of delta 12-PGJ2 induced HSP72 formation in HSC-I cells. HSP72 was also induced by heat shock treatment at 43 degrees C for 90 min. The quantity of HSP72 produced was markedly decreased by co-treatment with 1 microgram/ml of cycloheximide in delta 12-PGJ2-treated cells, and similarly reduced in HSC-I cells following heat treatment. Immunofluorescence using a monoclonal antibody to HSP72 demonstrated that HSP72 was localized mainly in the cytoplasm of HSC-I cells. Following treatment with 5 micrograms/ml of delta 12-PGJ2, however, HSP72 was found in the nucleolus as well as in the cytoplasm. The accumulation of HSP in the nucleolus was similarly prominent in HSC-I cells after treatment at 43 degrees C for 90 min. Addition of delta 12-PGJ2 to confluent HSC-1 cells resulted in the disappearance of actin filaments and the disarrangement of keratin filaments, as visualized with fluorescent-labeled phallacidine or immunofluorescence. These results suggest that the cytotoxicity of cyclopentenone PG is related to the induction of HSP72, and to cytoskeleton damage in transformed human epidermal cells in culture.
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PMID:Induction of 72-kD heat shock protein and cytoskeleton damage by cytotoxic prostaglandin delta 12-PGJ2 in transformed human epidermal cells in culture. 137 19

The effects of prostaglandins (PGs) A and J, which are anti-tumor eicosanoids, on the proliferation of cultured vascular smooth muscle cells were investigated. Serum-stimulated DNA synthesis was potently inhibited by PGA1, PGA2, PGJ2, and delta 12-PGJ2 in similar dose-dependent fashions. The effects of PGA1 and PGA2 were reversible when they were removed from the culture media, whereas recoveries were only partial in the cells treated with PGJ2 and delta 12-PGJ2. PGs were effective even if they were added immediately before entry into S phase. Inhibition of DNA synthesis was sustained when hydroxyurea, which blocks cell cycle at the G1/S border, was added after the removal of PGA2, and vice versa; PGs blocked DNA synthesis when they were added after the removal of hydroxyurea. Levels of c-myc mRNA formed two peaks during the G1 phase, at 1-2 h and at 8-12 h. The PGs did not affect the first elevation, but enhanced the second and sustained it up to 18-24 h, whereas in controls, c-myc mRNA decreased quickly after entry into S phase. The rate of degradation of c-myc mRNA was much smaller in PG-treated cells than in nontreated cells. We conclude, therefore, that PGA and PGJ inhibit a crucial event(s) in the cell cycle occurring at the G1/S border, but that this inhibition is not accompanied by the reduction in c-myc gene expression in contrast with some types of tumor cells treated with PGs.
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PMID:Prostaglandins A and J arrest the cell cycle of cultured vascular smooth muscle cells without suppression of c-myc expression. 157 2

Cyclopentenone prostaglandins (PGs) such as delta 12-PGJ2 and PGA are potent inducers of growth inhibition in a variety of cultured cells, including epidermal cells. These PGs are actively transported into cells by a specific carrier on cell membrane and accumulate in cell nuclei with binding to nuclear protein. To clarify the mechanism of cytotoxicity of these PGs in epidermal cells, we examined the effects of delta 12-PGJ2 on protein synthesis and cytoskeleton in the PAM 212 transformed mouse epidermal cell line. Cycloheximide at 1 microgram/ml culture medium exhibited a protective effect on cell growth inhibition of PAM 212 cells by delta 12-PGJ2. The analysis of cell lysate protein patterns by SDS-polyacrylamide gel electrophoresis revealed that 12-h incubation with delta 12-PGJ2 increased the amount of 70 kD protein in PAM 212 cells. The amount of 70 kD protein in delta 12-PGJ2-treated cells was markedly decreased by cotreatment with cycloheximide. This 70 kD protein was also induced in PAM 212 cells with treatment at 43 degrees C for 90 min, indicating that this synthesized protein belongs to the heat shock protein. The addition of delta 12-PGJ2 to confluent PAM 212 cells resulted in the disappearance of action filament, as visualized by fluorescent labeled phallacidine, but in contrast, keratin filament appeared to be intact during 12-h incubation with delta 12-PGJ2 at a concentration of 5 micrograms/ml culture medium. These results suggest that the cytotoxicity of cyclopentenone PGs is at least in part due to induction of the synthesis of some protein(s), probably one of the heat shock proteins, and the damage to the actin filament in transformed cultured epidermal cells.
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PMID:Effects of cytotoxic prostaglandin, delta 12-PGJ2 on protein synthesis and cytoskeleton in transformed epidermal cells in culture. 169 39

Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ2, and delta 12-PGJ2, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA2 and delta 12-PGJ2 in primary cultures of purified rat hepatocytes. As a model ligand, [3H]PGA1 bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 microM (low affinity). The high-affinity binding of [3H]PGA1 was 9- and approximately 13-fold more avid than the binding of the conventional fatty acid ligands, oleic acid and arachidonic acid, respectively. The abilities of different prostaglandins to compete with the high-affinity binding of [3H]PGA1 correlated with their growth inhibitory activities reported previously and here. The growth inhibitory cyclopentenone prostaglandins (PGA1, PGA2, delta 12-PGJ2, and PGJ2) were the best competitive ligands, intermediate competitors were the weak growth inhibitors PGE1 and PGD2, and the poorest competitors were PGE2 and PGF2 alpha, which stimulate rather than inhibit DNA synthesis in rat hepatocytes in primary culture. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.
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PMID:Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen. 225 Dec 82

Prostaglandins (PGs) are bioregulatory substances and are widely distributed in a variety of tissues. Numerous facts have been described in relation to cancer biology with PGs. The purpose of our study lies in the creation of anti-tumor PGs. We have described that PGD2 has strong cell growth inhibitory activity; furthermore, we discovered that PGJ2, 9-deoxy-delta 9-PGD2, has 3 times stronger activity than the mother compound, PGD2. In vivo experiments showed that only PGA2 and PGJ2 exert antitumor activity. Thus, cyclopentenone ring structure in PG seems to be an essential moiety for cytotoxicity of PG. On the basis of the above facts, we propose tha name of antineoplastic PGs for PGA and PGJ derivatives which have cyclopentenone ring. Recently, we developed several antineoplastic PGs which showed IC50 value less than 0.3 microgram/ml against L1210 leukemia cells, and these compounds also showed antitumor activity against Ehrlich ascites tumor in vivo comparable to that of cyclophosphamide. The action mechanism seems to be in its alkylation activity of the cyclopentenone structure and not in receptor-cAMP route. Spectrum of anti-tumor activity and its toxicity in vivo are now under investigation. In this brief review, mainly our recent approaches in this field are discussed.
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PMID:[Development of antineoplastic prostaglandins]. 657 12

Cyclopentenone prostaglandins PGA1 and PGJ2 induce growth arrest at the G1/S interphase of the cell cycle in tumour cell lines. Notably, PGE, the precursor molecule of PGA, downregulates the interleukin (IL)-2-dependent proliferation of lymphocytes. Therefore the IL-2/IL-2 receptor system and relative signal transduction is a possible target of the antiproliferative effect of PGA/PGJ. In the present study the PGA1/PGJ2-dependent growth inhibition of IL-2-stimulated primary human cord blood mononuclear cells (CBMCs) was found to be mediated by interference with the IL-2 proliferative signal. Both prostaglandins (PGs) inhibited the synthesis of total RNA and protein in IL-2 stimulated cells. PGA1 and even more PGJ2 downregulated the expression of IL-2 receptor alpha (CD25 phenotype). IL-2 partly reversed this effect. Moreover, suppression of IL-2-stimulated cells was not the result of PG-mediated activation of apoptosis. On the contrary, PGs reduced both apoptosis and the high expression of c-Jun detectable in CBMCs spontaneously. Cyclin A/Cdk2 complexes regulate G1/S transition during the cell cycle. In IL-2-stimulated cells, the levels of Cdk2 were found to be lower in PG-treated cells than those detected in controls. In conclusion, cyclopentenone PGs inhibit CBMCs spontaneous or IL-2-dependent proliferation in part by interfering with the IL-2 pathway.
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PMID:Functional antagonism between IL-2 and PGA1 or PGJ2 in the control of proliferation of human cord blood-derived mononuclear cells. 908 5

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