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This Article Accepted manuscript (PDF) Supplementary Data All Versions of this Article: JME-08-0182v1 JME-08-0182v2    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Udelhoven, M. Articles by Schubert, M. PubMed PubMed Citation Articles by Udelhoven, M. Articles by Schubert, M.

M Udelhoven, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
U Leeser, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
S Freude, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
M Hettich, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
M Laudes, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
J Schnitker, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
W Krone, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany
M Schubert, Department of Internal Medicine II, University of Cologne, Cologne, 50937, Germany

Markus Schubert, Email: markus.schubert{at}uni-koeln.de

Abstract

The insulin receptor substrates (IRS) 1-4 are adaptor proteins mediating effects of insulin and IGF-1. IRS-2 is critical for hepatic glucose metabolism and liver carcinogenesis since 80% of human hepatocellular carcinomas (HCC) overexpress IRS-2. We identified a region 688 bp upstream of the translation start codon responsible for ~90% of basal human IRS-2 promoter activity in liver. SP1 and NF1 were found to bind in this region. Mutation of both binding sites or inhibition of ERK suppressed IRS-2 promoter activity almost completely revealing a major role of MAP kinases for IRS-2 transcription. Oxidative stress increased IRS-2 promoter activity and endogenous IRS-2 expression. Similar to the LDL receptor, IRS-2 promoter activity raised even more after additional inhibition of p38MAPK indicating an inhibitory effect of p38MAPK on ERK mediated IRS-2 transcription. Activation of the MAPK pathway using IL-1β increased IRS-2 promoter activity similar to oxidative stress. In contrast IL-1β decreases and inhibition of the MAPK pathway increases IRS-1 promoter activity, revealing opposed effects on the expression of different IRS proteins.We conclude, that the identified region (-688 to -611 bp) in the human IRS-2 promoter is essential for stress induced transcription, which depends on both ERK activation as well as SP1 and NF1 binding.