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Disparate Effects of Thyroid Hormone on Actions of Epidermal Growth Factor and Transforming Growth Factor- Are Mediated by 3',5'-Cyclic Adenosine 5'-Monophosphate-Dependent Protein Kinase II

Research Service, Stratton Veterans Affairs Medical Center, the Ordway Research Institute, Inc., and the Wadsworth Center, New York State Department of Health, Albany, New York 12208

Address all correspondence and requests for reprints to: Paul J. Davis, M.D., Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208. E-mail: pjdavis{at}albany.net.

Epidermal growth factor (EGF) and TGF share the same plasma membrane receptor. In the present studies in HeLa cells, both EGF and TGF caused MAPK (ERK1/2) activation and expression of the immediate-early gene c-fos. Thyroid hormone (T₄) nongenomically enhanced EGF- and TGF-induced MAPK activation. This T₄ action was duplicated by T₄-agarose and blocked by tetraiodothyroacetic acid, which inhibits binding of T₄ to plasma membranes. TGF-induced MAPK activation was potentiated by 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) but not 8-chloro-cyclic adenosine monophosphate. TGF, T₄, and 8-Br-cAMP each caused protein kinase A (PKA) II serine phosphorylation, whereas phosphorylation of PKA-II was not seen in cells treated with EGF or 8-chloro-cyclic adenosine monophosphate. In a PKA activity assay, the enzyme was stimulated by T₄, EGF, and TGF; T₄ enhanced the effect of TGF but not that of EGF. T₄, although it potentiated c-fos gene expression in EGF-treated cells, suppressed this effect in cells treated with TGF. Cells exposed to 8-Br-cAMP also inhibited TGF-stimulated c-fos expression. Studies of cell proliferation indicated that T₄ potentiated EGF action but inhibited that effect in TGF-treated cells. The disparate effects of T₄ on actions of EGF and TGF, which share the same cell surface receptor, are mediated by hormone phosphorylation and activation of PKA-II.

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