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Atypical Protein Kinase C- Stimulates Thyrotropin-Independent Proliferation in Rat Thyroid Cells¹

Center for Experimental Therapeutics (N.F., M.J.C., M.G.K.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160; Department of Pharmacology (G.V.P., J.L.M., M.G.K.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084

Address all correspondence and requests for reprints to: Marcelo G. Kazanietz, Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Biomedical Research Building II/III, Philadelphia, Pennsylvania 19104-6160. E-mail: marcelo{at}spirit.gcrc.upenn.edu or Judy L. Meinkoth, Department of

Several reports have indicated that protein kinase C (PKC) is an important regulator of proliferation in thyroid cells. Unlike TSH, the mitogenic effects of phorbol esters are accompanied by de-differentiation. The role of individual PKC isoforms in thyroid cell proliferation and differentiation has not been examined. Recent studies have implicated the atypical PKC, a phorbol ester-unresponsive isozyme, in cell proliferation, death, and survival. We overexpressed PKC in Wistar rat thyroid (WRT) cells and determined that PKC conferred TSH-independent DNA synthesis and cell proliferation. Cells overexpressing PKC show higher levels of phosphorylated p42/p44 MAPK compared with vector-transfected cells. Experiments using a luciferase reporter for Elk-1 revealed that PKC overexpressing cells exhibit higher basal Elk-1 transcriptional activity than vector-transfected control cells. Interestingly, stimulation of Elk-1 transcriptional activity by MEK1, a p42/p44 MAPK kinase, was significantly enhanced in cells overexpressing PKC. Strikingly, TSH retained the ability to stimulate Tg expression in cells expressing PKC. These results suggest that PKC stimulates TSH-independent mitogenesis through a p42/p44 MAPK-dependent pathway. Unlike overexpression of Ras or phorbol ester treatment, PKC overexpression does not impair thyroglobulin (Tg) expression.

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