RGD Reference Report - The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-beta I and -delta. - Rat Genome Database

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The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-beta I and -delta.

Authors: Goldberg, HJ  Whiteside, CI  Fantus, IG 
Citation: Goldberg HJ, etal., J Biol Chem 2002 Sep 13;277(37):33833-41.
RGD ID: 729915
Pubmed: PMID:12105191   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M112331200   (Journal Full-text)

Increased flux through the hexosamine biosynthesis pathway (HBP) has been shown to stimulate the expression of a number of genes. We previously demonstrated in glomerular mesangial and endothelial cells that both high glucose concentrations and glucosamine activated the plasminogen activator inhibitor-1 (PAI-1) gene promoter through the transcription factor, Sp1; and that the glutamine:fructose-6-phosphate amidotransferase inhibitor, 6-diazo-5-oxonorleucine, inhibited the effect of high glucose, but not that of glucosamine. Here, we examined the role of protein kinase C (PKC) isoforms in the regulation of the PAI-1 promoter and Sp1 transcriptional activity by the HBP. In transient transfections, exposure to 2 mm glucosamine or 20 mm glucose for 4 days increased the activities of a PAI-1 promoter-luciferase reporter gene as well as the Sp1 transcriptional activation domain fused to the GAL4 DNA-binding domain cotransfected with a GAL4 promoter-luciferase reporter. Cotransfected dominant negative PKC-betaI and -delta completely blocked the induction of PAI-1 promoter transcription by both sugars, whereas only dominant negative PKC-betaI interfered with Sp1-GAL4 activation. Both glucosamine and high glucose stimulated the in vitro kinase activity of immunoprecipitated PKC-betaI and -delta. Furthermore, 6-diazo-5-oxonorleucine suppressed high glucose-induced PKC kinase activity and Sp1-GAL4 transcriptional activation. These findings demonstrate a requirement for the PKC-betaI and -delta signal transduction pathways in HBP-induced transcription.

Objects referenced in this article
Gene Prkcb protein kinase C, beta Rattus norvegicus
Gene Prkcd protein kinase C, delta Rattus norvegicus
Gene Serpine1 serpin family E member 1 Rattus norvegicus

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