Role of the Different Mitogen-Activated Protein Kinase Subfamilies in the Stimulation of Dog and Human Thyroid Epithelial Cell Proliferation by Cyclic Adenosine 5′-Monophosphate and Growth Factors

• Published in: Endocrinology (Philadelphia) 2003-04, Vol.144 (4), p.1341-1349
• Main Authors: Vandeput, Fabrice, Perpete, Sandrine, Coulonval, Katia, Lamy, Françoise, Dumont, Jacques E
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acetic acid; Adenosine kinase; Adenosine monophosphate; AKT protein; Animals; Arsenites - pharmacology; Biological and medical sciences; c-Jun protein; Carcinogens - pharmacology; Cell Division - drug effects; Cell Division - physiology; Cell proliferation; Cells, Cultured; Colforsin - pharmacology; Cyclic AMP; Cyclic AMP - metabolism; Deoxyribonucleic acid; DNA; DNA biosynthesis; Dogs; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; Epidermal growth factor; Epidermal Growth Factor - pharmacology; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - enzymology; Epithelium; Flavonoids - pharmacology; Forskolin; Fundamental and applied biological sciences. Psychology; Growth factors; Hepatocyte growth factor; Hepatocyte Growth Factor - pharmacology; Humans; Hypoglycemic Agents - pharmacology; Imidazoles - pharmacology; Insulin; Insulin - pharmacology; JNK protein; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Phorbol 12-myristate 13-acetate; Phosphorylation; Protein biosynthesis; Proteins; Pyridines - pharmacology; Sodium Compounds - pharmacology; Synthesis; Tetradecanoylphorbol Acetate - pharmacology; Thyrocytes; Thyroid; Thyroid gland; Thyroid Gland - cytology; Thyroid-stimulating hormone; Thyrotropin - pharmacology; Transcription factors
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2001-211316

We have investigated the role of the different classes of MAPKs, i.e. ERKs, c-Jun N-terminal kinases (JNKs), and p38 MAPK in the proliferation of dog and human thyroid epithelial cells (thyrocytes) in primary cultures. In these cells, TSH, acting through cAMP, epidermal growth factor, hepatocyte growth factor (HGF), and phorbol 12-myristate 13-acetate induce DNA synthesis. With the exception of HGF, all of these factors require the presence of insulin for mitogenic effects to be expressed. We found that TSH and forskolin are without effect on the phosphorylation and activity of the different classes of MAPKs. In contrast, all the cAMP-independent growth factors, whereas without effect on the phosphorylation and activity of JNKs and p38 MAPK, stimulated the ERKs. This effect was strong and sustained in response to HGF, epidermal growth factor and 12-myristate 13-acetate but weak and transient in response to insulin. Moreover, whereas in stimulated cells DNA synthesis was inhibited by PD 098059, an inhibitor of MAPK kinase 1 and consequently of ERKs, it was not modified by SB 203580, an inhibitor of p38 MAPK. Taken together, these data 1) exclude a role of JNKs and p38 MAPK in the proliferation of dog and human thyrocytes; 2) suggest that the mitogenic action of the cAMP-independent agents requires a strong and sustained activation of both ERKs and phosphatidylinositol 3-kinase/protein kinase B as realized by HGF alone or by the other agents together with insulin; and 3) show that TSH and cAMP do not activate ERKs but that the weak activation of ERKs by insulin is nevertheless necessary for DNA synthesis to occur.