Epidermal growth factor receptor-induced activator protein 1 activity controls density-dependent growth inhibition in normal rat kidney fibroblasts.
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 densitydependent 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.
Hornberg
Jorrit J
JJ
Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, the Netherlands. jorrit.hornberg@organon.com
Dekker
Henk
H
Peters
Peter H J
PH
Langerak
Petra
P
Westerhoff
Hans V
HV
Lankelma
Jan
J
van Zoelen
Everardus J J
EJ
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D007668:Kidney / Q000166:cytology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000819:agonists / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D018808:Transcription Factor AP-1; D014212:Tretinoin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases