The proliferation of most normal cells depends on the co-operation of several growth factors and hormones, each with a specific role, but the key events involved in the action of each necessary stimulant remain largely uncharacterized. In the present study, the pathways involved in the mechanism(s) of co-operation have been investigated in primary cultures of dog thyroid epithelial cells. In this physiologically relevant system, thyroid stimulating hormone (TSH) acting through cAMP, epidermal growth factor (EGF) and phorbol esters (such as PMA) induce DNA synthesis. Their effect requires stimulation of the insulin-like growth factor-1 (IGF-1) receptor by either IGF-1 or insulin, which are not themselves mitogenic agents. In contrast, hepatocyte growth factor (HGF) is itself fully mitogenic. The results of the study demonstrate that cAMP, EGF, HGF and PMA stimulate p70 ribosomal S6 kinase (p70 S6 kinase). However, insulin/IGF-1 also stimulate p70 S6 kinase. Thus stimulation of p70 S6 kinase might be necessary, but is certainly not sufficient, for the induction of DNA synthesis and is not specific for any stimulated pathway. In contrast, phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (PKB) activation by insulin and HGF is strong and sustained, whereas it is weak and transient with EGF and absent in the presence of TSH or PMA. These findings suggest that: (i) stimulation of PI 3-kinases and/or PKB is not involved in the cAMP-dependent pathways leading to thyrocyte proliferation, or in the action of PMA, (ii) the stimulation of the PI 3-kinase/PKB pathway may account for the permissive action of insulin/IGF-1 in the proliferation of these cells, and (iii) the stimulation of this pathway by HGF may explain why this agent does not require insulin or IGF-1 for its mitogenic action.
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June 2000
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Research Article|
May 23 2000
Phosphatidylinositol 3-kinase, protein kinase B and ribosomal S6 kinases in the stimulation of thyroid epithelial cell proliferation by cAMP and growth factors in the presence of insulin
Katia COULONVAL;
*Institute of Interdisciplinary Research, Free University of Brussels, Campus Erasme, Route de Lennik 808, B-1070 Brussels, Belgium
1To whom correspondence should be addressed (e-mail [email protected]).
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Fabrice VANDEPUT;
Fabrice VANDEPUT
2
†Ludwig Institute for Cancer Research and Department of Oncology, University College London, 91 Riding House Street, London WIP 8BT, U.K.
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Rob C. STEIN;
Rob C. STEIN
†Ludwig Institute for Cancer Research and Department of Oncology, University College London, 91 Riding House Street, London WIP 8BT, U.K.
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Sara C. KOZMA;
Sara C. KOZMA
‡Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland
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Françoise LAMY;
Françoise LAMY
*Institute of Interdisciplinary Research, Free University of Brussels, Campus Erasme, Route de Lennik 808, B-1070 Brussels, Belgium
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Jacques E. DUMONT
Jacques E. DUMONT
*Institute of Interdisciplinary Research, Free University of Brussels, Campus Erasme, Route de Lennik 808, B-1070 Brussels, Belgium
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Publisher: Portland Press Ltd
Received:
January 04 2000
Revision Received:
March 09 2000
Accepted:
March 24 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 348 (2): 351–358.
Article history
Received:
January 04 2000
Revision Received:
March 09 2000
Accepted:
March 24 2000
Citation
Katia COULONVAL, Fabrice VANDEPUT, Rob C. STEIN, Sara C. KOZMA, Françoise LAMY, Jacques E. DUMONT; Phosphatidylinositol 3-kinase, protein kinase B and ribosomal S6 kinases in the stimulation of thyroid epithelial cell proliferation by cAMP and growth factors in the presence of insulin. Biochem J 1 June 2000; 348 (2): 351–358. doi: https://doi.org/10.1042/bj3480351
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