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Title: Insulin induces a transcriptional activation of epiregulin, HB-EGF and amphiregulin, by a PI3K-dependent mechanism: Identification of a specific insulin-responsive promoter element

Abstract

Previously we have shown that insulin-stimulation of RT4 bladder cancer cells leads to increased proliferation, which require HER1 activation, and is accompanied by increased mRNA expression of the EGF-ligands heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), and epiregulin (EPI) [D. Ornskov, E. Nexo, B.S. Sorensen, Insulin-induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system, FEBS J. 273 (2006) 5479-5489]. In the present paper, we have investigated the molecular mechanism leading to this insulin-induced expression. We monitored the decay of mRNA after inhibiting transcription with Actinomycin D and demonstrated that the insulin-mediated increase was not caused by enhanced mRNA stability. In untreated cells, HB-EGF mRNA was the least stable, whereas AR and EPI mRNA decayed with slower kinetics. However, promoter analysis of HB-EGF and EPI demonstrated that insulin stimulated transcription. Studies on the EPI promoter identified the insulin-responsive element to be located in the region -564 to -365 bp. This region contains potential binding sites for the transcription factors SP1, AP1, and NF-{kappa}B. Interestingly, all three transcription factors can be activated by PI3K. We demonstrate that the insulin-induced expression of HB-EGF, AR, and EPI mRNA is completely prevented by the specific PI3K inhibitor Wortmannin,more » suggesting an involvement of the PI3K.« less

Authors:
 [1];  [1];  [2]
  1. Department of Clinical Biochemistry, Aarhus Sygehus University Hospital in Aarhus (Denmark)
  2. Department of Clinical Biochemistry, Aarhus Sygehus University Hospital in Aarhus (Denmark). E-mail: boess@as.aaa.dk
Publication Date:
OSTI Identifier:
20979840
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 354; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2007.01.047; PII: S0006-291X(07)00090-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTINOMYCIN; BLADDER; CELL PROLIFERATION; GROWTH FACTORS; HEPARIN; INSULIN; NEOPLASMS; PROMOTERS; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Ornskov, Dorthe, Nexo, Ebba, and Sorensen, Boe S. Insulin induces a transcriptional activation of epiregulin, HB-EGF and amphiregulin, by a PI3K-dependent mechanism: Identification of a specific insulin-responsive promoter element. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.01.047.
Ornskov, Dorthe, Nexo, Ebba, & Sorensen, Boe S. Insulin induces a transcriptional activation of epiregulin, HB-EGF and amphiregulin, by a PI3K-dependent mechanism: Identification of a specific insulin-responsive promoter element. United States. doi:10.1016/j.bbrc.2007.01.047.
Ornskov, Dorthe, Nexo, Ebba, and Sorensen, Boe S. Fri . "Insulin induces a transcriptional activation of epiregulin, HB-EGF and amphiregulin, by a PI3K-dependent mechanism: Identification of a specific insulin-responsive promoter element". United States. doi:10.1016/j.bbrc.2007.01.047.
@article{osti_20979840,
title = {Insulin induces a transcriptional activation of epiregulin, HB-EGF and amphiregulin, by a PI3K-dependent mechanism: Identification of a specific insulin-responsive promoter element},
author = {Ornskov, Dorthe and Nexo, Ebba and Sorensen, Boe S.},
abstractNote = {Previously we have shown that insulin-stimulation of RT4 bladder cancer cells leads to increased proliferation, which require HER1 activation, and is accompanied by increased mRNA expression of the EGF-ligands heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), and epiregulin (EPI) [D. Ornskov, E. Nexo, B.S. Sorensen, Insulin-induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system, FEBS J. 273 (2006) 5479-5489]. In the present paper, we have investigated the molecular mechanism leading to this insulin-induced expression. We monitored the decay of mRNA after inhibiting transcription with Actinomycin D and demonstrated that the insulin-mediated increase was not caused by enhanced mRNA stability. In untreated cells, HB-EGF mRNA was the least stable, whereas AR and EPI mRNA decayed with slower kinetics. However, promoter analysis of HB-EGF and EPI demonstrated that insulin stimulated transcription. Studies on the EPI promoter identified the insulin-responsive element to be located in the region -564 to -365 bp. This region contains potential binding sites for the transcription factors SP1, AP1, and NF-{kappa}B. Interestingly, all three transcription factors can be activated by PI3K. We demonstrate that the insulin-induced expression of HB-EGF, AR, and EPI mRNA is completely prevented by the specific PI3K inhibitor Wortmannin, suggesting an involvement of the PI3K.},
doi = {10.1016/j.bbrc.2007.01.047},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 354,
place = {United States},
year = {Fri Mar 23 00:00:00 EDT 2007},
month = {Fri Mar 23 00:00:00 EDT 2007}
}