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Epidermal growth factor receptor-induced activator protein 1 activity controls density-dependent growth inhibition in normal rat kidney fibroblasts

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Abstract

Density-dependent growth inhibition secures tissue homeostasis. Dysfunction of the mechanisms, which regulate this type of growth control is a major cause of neoplasia. In confluent normal rat kidney (NRK) fibroblasts, epidermal growth factor (EGF) receptor levels decline, ultimately rendering these cells irresponsive to EGF. Using an activator protein (AP)-1 sensitive reporter construct, we show that AP-1 activity is strongly decreased in density-arrested NRK cells, but is restored after relaxation of density-dependent growth inhibition by removing neighboring cells. EGF could not induce AP-1 activity or S-phase entry in density-arrested cells, but could do so after pretreatment with retinoic acid, which enhances EGF receptor expression. Our results support a model in which the EGF receptor regulates density-dependent growth control in NRK fibroblasts, which is reflected by EGF-induced mitogenic signaling and consequent AP-1 activity.

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Author notes

  1. Jorrit J. Hornberg

    Present address: Department of Molecular Pharmacology, N.V. Organon, Oss, The Netherlands

Authors and Affiliations

  1. Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, the Netherlands

    Jorrit J. Hornberg, Petra Langerak, Hans V. Westerhoff & Jan Lankelma

  2. Department of Medical Oncology, VU Medical Center, Amsterdam, the Netherlands

    Henk Dekker & Jan Lankelma

  3. Department of Cell Biology, Faculty of Science, University of Nijmegen, Nijmegen, the Netherlands

    Peter H. J. Peters & Everardus J. J. van Zoelen

  4. Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester, UK

    Hans V. Westerhoff

Authors
  1. Jorrit J. Hornberg
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  7. Everardus J. J. van Zoelen
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Correspondence to Jorrit J. Hornberg.

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Hornberg, J.J., Dekker, H., Peters, P.H.J. et al. Epidermal growth factor receptor-induced activator protein 1 activity controls density-dependent growth inhibition in normal rat kidney fibroblasts. Mol Biotechnol 34, 101–108 (2006). https://doi.org/10.1385/MB:34:2:101

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