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Thyrotropin Regulates c-Jun N-Terminal Kinase (JNK) Activity through Two Distinct Signal Pathways in Human Thyroid Cells¹

Department of Nature Medicine (T.H., H.N., T.-T.Y., S.Y.), Department of International Health and Radiation Research (N.T., S.Y.), Atomic Bomb Disease Institute, Department of Pharmacology (Y.N.), Nagasaki University School of Medicine, Nagasaki, 852-8523, Japan; Kuma Hospital (S.F., K.K.), Kobe, 650, Japan; Ito Hospital (N.I., K.I.), Tokyo, 150, Japan

Address all correspondence and requests for reprints to: Hiroyuki Namba, MD, Associate Professor, Department of Nature Medicine, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, 1–12-4 Sakamoto, Nagasaki 852, Japan. E-mail: namba{at}net.nagasaki-u.ac.jp

c-Jun N-terminal kinases (JNK) participate in cellular responses to mitogenic stimuli and environmental stresses. We investigated whether and how TSH, which promotes the proliferation and differentiation of thyroid cells, regulates JNK activity in primary cultured human thyroid cells. TSH stimulated JNK activity in cytosolic fractions of thyroid cells measured by in vitro kinase assay. A low concentration of TSH (10^-11 M) stimulated JNK activity but at a higher dose (10^-8–10^-7 M), TSH suppressed JNK activity without any change of JNK protein level. Activation of JNK by TSH was also observed in CHO cells stably transfected with TSH receptor complementary DNA (cDNA), suggesting a ligand-receptor specific interaction. TSH stimulated JNK activity through a pertussis toxin-sensitive pathway. We next elucidated the signal transduction pathways in TSH-induced JNK activation by examining the involvement of four distinct intracellular signal molecules; protein kinase C (PKC), cAMP, Ca²⁺, and PI3-kinase. The stimulation of JNK by TSH was blocked by two PKC inhibitors and suppressed by 8-bromo-cAMP or forskolin. These findings demonstrate that TSH regulates JNK activity biphasically in human thyroid cells through an interaction between Gi-PKC and cAMP-PKA pathways.

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