Epidermal growth factor receptor-induced activator protein 1 activity controls density-dependent growth inhibition in normal rat kidney fibroblasts |
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| Authors: | Jorrit J Hornberg Henk Dekker Peter H J Peters Petra Langerak Hans V Westerhoff Jan Lankelma Everardus J J van Zoelen |
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| Institution: | (1) Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, the Netherlands;(2) Department of Medical Oncology, VU Medical Center, Amsterdam, the Netherlands;(3) Department of Cell Biology, Faculty of Science, University of Nijmegen, Nijmegen, the Netherlands;(4) Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester, UK;(5) Present address: Department of Molecular Pharmacology, N.V. Organon, Oss, The Netherlands |
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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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| Keywords: | EGF receptor AP-1 density-dependent growth inhibition contact inhibition NRK fibroblasts GFP |
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