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      Induction of Transcription Factor AP-2 by Cytokines and Prostaglandins in Cultured Mesangial Cells

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          Background/aims: Activator protein-2 (AP-2) is an important transcription factor for activation of growth- and inflammatory-associated genes. To detect AP-2 in the mesangium, the expression level of AP-2 was examined in cultured mesangial cells in response to various cytokines and prostaglandins. The level was also observed in kidney tissue samples obtained from patients with proteinuria and from a rat nephrosis model. Methods: AP-2 was immunohistochemically detected with a specific antibody. The expression level was analyzed by immunoblotting. Human tissue samples were obtained from patients with proteinuria. Kidney samples were also obtained from rats with puromycin aminonucleoside-induced nephrosis. Results: Pro-inflammatory cytokines, such as IL-6, IL-1 and IL-2, but not TNF-α, induced AP-2 expression in a time- and dose-dependent manner in cultured mesangial cells. PGE<sub>2</sub> and PGI<sub>2</sub> also induced AP-2 expression, while PGF<sub>2α</sub> failed to induce this protein. High expression levels of AP-2 were observed in different cell types including mesangial cells of kidney samples from patients with proteinuria. Similar results were obtained from the rat nephrosis model. Conclusion: These findings demonstrate that the primary cytokines induce AP-2 protein in mesangial cells. AP-2 may act as a transcription factor to produce additional cytokines and growth-associated gene products, suggesting an important role for AP-2 for the function of mesangial cells in glomerular disorders.

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          Most cited references 4

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          Comparative analysis of AP-2 alpha and AP-2 beta gene expression during murine embryogenesis.

          Transcription factor AP-2 has been identified as playing important roles during embryonic development of the neural tube, neural crest derivatives, skin, and urogenital tissues. Recently, we isolated a second AP-2 transcription factor, AP-2 beta, which is 76% homologous to the previously known AP-2 alpha gene, and showed that both genes are coexpressed in murine embryos at day 13.5 and 15.5 post coitum (pc). In the current study, we used specific cRNA probes to study comparatively AP-2 alpha and AP-2 beta expression by in situ hybridization of murine embryonic tissue sections. Our results reveal that expression of both genes starts at day 8 pc in the lateral head mesenchyme and extraembryonic trophoblast. The expression pattern was identical until day 10 pc but diverged significantly during later stages of development. From day 11 forward, specific expression patterns of AP-2 alpha and AP-2 beta mRNA were observed. Specific AP-2 beta signals were detected in the midbrain, sympathetic ganglia, adrenal medulla, and cornea. Specific AP-2 alpha signals were present in the limb buds, dorsal root ganglia, tooth germs, and Moll's and Meibom's glands. In contrast, expression of both genes occurred in skin, facial mesenchyme, spinal cord, cerebellum, and renal tubular epithelia. Our results indicate that both genes are expressed with different temporal and spatial patterns during embryonic development.
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            Promoter-specific modulation of insulin-like growth factor II genomic imprinting by inhibitors of DNA methylation.

            The insulin-like growth factor II (IGF-II) gene is maternally imprinted in most normal tissues with only the paternal allele being transcribed. In several human tumors, however, IGF-II is expressed from both parental alleles. To explore the underlying mechanism of IGF-II imprinting, we have examined the effect of DNA demethylation in cultured human and mouse astrocyte cells. An increased expression of IGF-II was observed when these cells were treated with the DNA demethylating agents, 5-azacytidine or 2-deoxy-5-azacytidine. Allelic analysis indicated that, following DNA demethylation, the increment in IGF-II mRNA was primarily derived from the normally suppressed maternal allele. Examination of promoter usage revealed that only the most proximal promoter (mP3 in mouse and hP4 in human) responded to DNA demethylating agents, whereas the expression of IGF-II from the other promoters remained unchanged. The enhanced expression of IGF-II from these promoters suggests the presence of a methylation-response element in or near mP3 and hP4. This study indicates that DNA demethylating agents increase IGF-II expression primarily by stimulating the normally imprinted allele through the activation of the most proximal IGF-II promoter.
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              Regulation of the expression of the tissue transglutaminase gene by DNA methylation.

              We have investigated the role of DNA methylation in the regulation of the expression of the human tissue transglutaminase gene. Studies on the methylation of the transglutaminase promoter in normal and neoplastic human cells demonstrated that the promoter is methylated in vivo and hypomethylation of the promoter is correlated with constitutive gene expression. Demethylation of the promoter in vivo by treatment of the cells with 5-azacytidine increased transglutaminase expression and hypermethylation of the promoter in vitro suppressed its activity. These studies suggest that alternations in DNA methylation may be one of the mechanisms regulating the tissue-specific expression of the tissue transglutaminase gene.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                August 2001
                13 August 2001
                : 21
                : 4
                : 307-314
                Departments of aBiomolecular Sciences and bPediatrics, Fukushima Medical University School of Medicine, Fukushima, Japan
                46266 Am J Nephrol 2001;21:307–314
                © 2001 S. Karger AG, Basel

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                Figures: 7, References: 33, Pages: 8
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